TW200848019A - Aryl sulfonamides useful for modulation of the progesterone receptor - Google Patents

Abstract

In one embodiment, compounds of the following structure are described, wherein R1 to R7 are described herein. Also provided are methods for preparing these compounds and methods of contraception; treating or preventing fibroids; treating or preventing uterine leiomyomata; treating or preventing endometriosis, dysfunctional bleeding, and polycystic ovary syndrome; treating or preventing hormone-dependent carcinomas; providing hormone replacement therapy; stimulating food intake; synchronizing estrus; and treating cycle-related symptoms using the compounds described herein.

Description

200848019 IX. Description of the invention: [Technical field 3 of the invention] Field of the invention Arylsulfonamide for regulating a progesterone receptor. 5 [Prior Art] Background of the Invention Progesterone receptor (PR) agonists and antagonists, also known as PR modulators, have been described for contraception and various other indications. What is needed is a non-steroidal compound that is optionally used as a PR modulator. SUMMARY OF THE INVENTION In one aspect, compounds of the structure wherein RrR7 is as defined herein are illustrated.

In an additional aspect, providing contraception using the compounds described herein; treating or preventing fibroids; treating or preventing uterine leiomyomata; treating or preventing endometrial tissue dysfunction, dysfunction Sexual bleeding, and polycystic ovarian syndrome; treatment or prevention of hormone-dependent cancer; provision of hormone replacement therapy; stimulation of food intake; synchronization of estrus; and treatment of cycle-related symptoms. In another aspect, the method for the preparation of the compound of the following structure 200848019 is illustrated as being herein defined.

Other aspects and advantages of the invention will be apparent from the following detailed description of the invention. t. Performing a cold type] Detailed Description of the Preferred Embodiment A compound which is a modulator of a progesterone receptor is provided. These compounds are those having the formula I and having the following structure:

Wherein, the core and the 112 are respectively selected from the group consisting of: hydrazine, CiiC6 alkyl, substituted (^ to (6 alkyl, (: 3 to 〇: 8-cycloalkyl, substituted C3 to C8 cycloalkane 15) Alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, C3 to C6 alkenyl, c3 to c6 substituted alkenyl, c3 to C6 alkyne Substituted, substituted CdC6 alkynyl, -(CHmXn)zCHpXq, 0-Q to C6 alkyl ' 0-CjC6 substituted alkyl, and 〇_(CHmXn)zCHpXq; or heart and ruler 2 together form a a ring of 4 to 8 ring atoms having a carbon atom and 1 to 4 N, 〇, S, or S〇2 in its 20 main chain, and any c 200848019 atom or N atom system of the ring is selectively ^ to (: 4 alkyl, F, or CF3 substituted; R3, R4, R5 and R6 are additionally selected from: hydrazine, halogen, CN, C^C6 alkyl, substituted (^ to ( : 6 alkyl, -(CHmXn)zCHpXq, C3 to C6 cycloalkyl, substituted C3 to C6 cycloalkyl, O-QSQ alkyl, -(^ to 5 C6 substituted alkyl, 〇H, NH2,NH-(CHmXn)zCHpXq, 0_(CHmXn)zCHpXq, N-{(CHmXn)zCHpXq}2, aryl, substituted aryl, hetero a substituted heteroaryl, a heterocyclic ring, and a substituted heterocyclic ring; X-based halogen; m and η are 0 to 2, respectively, but conditionally m + n = 2; p and q are 0, respectively. To 3, but with the proviso that p + q = 3; z is 0 to 10; R7 is selected from 10, CjC6 alkyl, substituted CjC6 alkyl, c3 to c6 cycloalkyl, and substituted C3 To a C6 cycloalkyl group; or a pharmaceutically acceptable salt, tautomer, metabolite or prodrug thereof. In one embodiment, R? is a branched (^ to a decyl group. In one embodiment, 'R3, R4, R5, and R6 are ruthenium. In one additional embodiment, 15 R4 is ruthenium or halogen. In still another embodiment, rs is η or NF. In one embodiment, R? is CH3. In still another embodiment, R7 is (^ to (6 alkyl). In still another embodiment, (^ to decyl. In one embodiment, I is η, (^ to ^ alkyl, substituted by <^ to (: 6 alkyl, a to C6 cycloalkyl, or CF3. 20 in another embodiment, h system CH^C: 3 to Q cycloalkyl. In still another embodiment, R3 or R6 is NH-(CHmXn)zCHpXp, for example: NH(Cj C6 alkyl). In a further embodiment, & or & is N{(CHmXn)zCHpXq}2, for example: N{(CjC6 alkyl)} 2, wherein the q to C6 alkyl groups may be the same or different. In yet another embodiment, 200848019, RjnR2 is combined to form a scorpion, a scorpion, a tetrahydro urethane, a phoenix, or a bismuth. In a further embodiment, R3 or Ruler 6 is hydrazine, halogen, OCF3, CF3, or N(CH3)2. In still another embodiment, R4 and R6 are respectively Η or F. In a further embodiment, the R3 system is oxime or OCF3. In still another embodiment, R4 and R6 are respectively deuterium or F. In another embodiment, R4 and R5 are respectively Η or F. In still another embodiment, R5 is Η, CF3, N(CH3)2, or F. In a further embodiment, the hydrazine system or (^ to (6 alkyl; R2 hydrazine, (^ to decyl, substituted (^ to C6 alkyl, or C3SC6 cycloalkyl; or RjnR2 is combined with a ruthenium atom to form a tetrahydrogen. Bilo, σchen bite, tetrahydro-Chenchen, holphalin, or σbiluo; r4 and R5 are respectively η or F; R3 and R6 are respectively Is ruthenium, halogen, CF3, OCF3, or N(CH3)2; or RACjC6 alkyl. The inventors have discovered that the compounds described herein act not only as effective PR modulators, but also have improved solubility when In contrast to the other 15 PR modulators in the art, in addition, the compounds described herein have excellent bioavailability when administered in vivo and are selective for other nuclear hormone receptors. The compounds may contain one or more asymmetric centers and thus optical and non-image isomers. These compounds 20 may include optical isomers and non-image isomers; racemic and Divided, mirror-isolated pure R and S stereoisomers; other R and S stereoisomers a mixture; and a pharmaceutically acceptable salt thereof. The term π alkyl ' is used herein to refer to both straight-chain and branched saturated aliphatic hydrocarbon groups. In one embodiment, one The alkyl group has from 1 to 200848019 of about 8 carbon atoms (ie, Q, C2, C3, C4, C5, C6, C7, or 〇8). In another embodiment, the monoalkyl group has 1 to about 6 carbon atoms (ie, C, C2, C3, C4, C5 or C6). In one additional embodiment, the monoalkyl group has from 1 to about 4 carbon atoms (ie, Q, C2, .5 C3*C4). In still another embodiment, the monoalkyl group has from 1 to 4 carbon atoms (ie, C!, c2, or c4). The term ''loop An alkyl group is used herein to refer to a cyclic, saturated aliphatic hydrocarbon group. In one embodiment, a cycloalkyl group has from 3 to about 8 carbon atoms (ie, c3, c4). , c5, c6, c7, or c8). In another 10 embodiment, one cycloalkyl group has from 3 to about 6 carbon atoms (ie, C3, C4, C5 or C6). In an additional embodiment Medium, one A cycloalkyl group has from 3 to 6 carbon atoms (ie, C3, C4, (:5 or (:6). The term 'alkenyl'' is used herein to refer to having one or more carbon-carbons. Both a straight chain of a double bond and a branched alkyl group. In one embodiment, the 15-alkenyl group contains from 3 to about 8 carbon atoms (ie, C3, C4, C5, C6, C7, Or C8). In another embodiment, the monoalkenyl group has 1 or 2 /' carbon-carbon double bonds and 3 to about 6 carbon atoms (i.e., C3, C4, C5 or C6). In a further embodiment, the monoalkenyl group has 1 or 2 carbon-carbon double bonds and 3 to 6 carbon atoms (ie, C3, C4, C5 or C6). The term "π alkynyl" is used herein to refer to both straight-chain and branched alkyl groups having one or more carbon-carbon triple bonds. In one embodiment, the alkynyl group has 3 to about 8 carbon atoms (ie, C3, C4, C5, C6, C7, or C8). In another embodiment, the alkynyl group contains 1 or 2 carbon-carbon triple bonds and 3 Up to about 6 carbon atoms (ie, C3, C4, C5 or C6). In an additional embodiment, 200848019, an alkynyl group contains 1 or 2 carbon-carbon triple bonds and 3 to 6 carbon atoms. (ie, c3, c4, c5*c6). The terms "substituted alkyl", "substituted alkenyl", substituted substituted alkynyl, and "substituted cycloalkyl" are used. Reference is made to alkyl, alkenyl, alkynyl, and cyclo5 alkyl groups, each having one, two or more substituents selected from, but not limited to, hydrogen, halogen, CN, respectively. 0H, n02, cycloalkyl, amine, aryl heterocycle, aryl, alkoxy (alk〇xy), aryloxy, alkyloxy, fenyl, thiol, amine And an arylthio group. In one embodiment One or more carbon atoms in the monoalkyl group have two or more substituents. The term "arylthio" as used herein refers to an S(aryl) group, the point of attachment is via The sulfur atom and the aryl group can be substituted as indicated above. The term "alk〇xy" as used herein refers to a point in which a fluorene (alkyl) group is attached via an oxygen atom. And the alkyl group can be substituted as described above. The term "aryloxy" as used herein, refers to a fluorenyl (aryl) group, the point of attachment is via an oxygen atom and an aryl group. The group can be substituted as indicated above. The term, alkylcarbonyl, as used herein, refers to a point in which the c(o)(alkyl) group is attached via a carbon atom of the carbonyl moiety and the alkyl group energy 20 is as indicated above. of. The term 'alkylcarboxy" as used herein refers to a point in which the c(o)o(alkyl) group is attached via a carbon atom of the carboxyl moiety and the alkyl group can be substituted as indicated above. As used herein, the term "alkylamino" refers to both secondary and tertiary amines 228 200848019, the point of attachment via a nitrogen atom and the alkyl groups can be substituted as indicated above. The groups may be the same or different. The term "quote" as used herein refers to C1, Br, F, or a working group. 5 As used herein, the term ''aryl,' refers to a An aromatic, carbocyclic system of, for example, about 6 to 14 carbon atoms, which can include - a single ring or a polyaromatic ring bonded or linked together, at least a portion of a fused or linked ring forming a conjugated Aromatic systems. Aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, phenanthryl, anthracenyl, benzonaphthyl, with 10 and fluorenyl. Substituted radicals refer to an aryl group substituted by one or more substituents, including: halogen, CN, OH, oxime 02, amine, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy (alk〇Xy), (^ to (:3 perfluoroalkyl, <^ to (:3 perfluoro) Alkoxy, aryloxy, alkoxy including -0-(Clsc1()alkyl) or 15-indolyl (ci to c1() substituted alkyl), including -(:〇-((: Alkylcarbonyl group of 1 to (:10 alkyl) or -CCKCiSCw substituted alkyl), including alkyl) or alkyl group of -COCKQSCio substituted alkyl), _C(NH2)=N-OH, _S02 -(CeC1()alkyl), -S02-(Cj c10 substituted alkyl), -0-CH2-aryl, alkylamino, arylthio, aryl 20, or heteroaryl, these The group may be substituted. Desirably, a substituted aryl is substituted with from 1 to about 4 substituents. The term "heterocycle" or "heterocyclic" as used herein. '' can be used interchangeably to refer to a stable, saturated or partially unsaturated 3- to 9-membered monocyclic or polycyclic heterocyclic ring. Heterocyclic ring 11 200848019 in its A chain has a carbon atom and a hetero atom including nitrogen, oxygen, and a sulfur atom. In one embodiment, the main chain of the heterocyclic ring is 1 to large and has 4 hetero atoms. When the heterocyclic ring is at 0 士 & 々*, ^, the primary bond contains a nitrogen or sulfur atom. 5 10 15 20 L The mouse can be oxidized. The term or, hetero (4) (4) - also refers to a polycyclic ring, which is fused to about 6 to about 14 carbon atoms. The wire ring. The heterocyclic ring is attached to the aryl ring by providing a structure in which the ring system is formed by chemically stable one or more T atoms or carbon atoms. In one embodiment, the heterocyclic ring comprises a polycyclic ring system having from 1 to 5 rings. • Various heterocyclic groups are known in the art and include, without limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings, mixed ', sub-rings, thick containing heteroatoms Ring, and combinations of them. Examples of heterocycles include, but are not limited to, tetrahydrofuranyl, thiol, 2-oxooxythiol, pyrrolidinyl, morpholinyl, indolofosyl, thiafosolinyl Sulfone, piperidyl, pyronyl, di〇xinyl, dipyridyl, dithiolyl, oxythiol, diggyr, % serazolyl,唠耕基, oxathiazinyl, stupid and chlorinated, stupid and arable, and sylvan. The term "heteroaryl" as used herein refers to a stable aromatic, to monocyclic or polycyclic ring containing a hetero atom. A heteroaryl ring has a carbon atom in its main chain and one or more heteroatoms including nitrogen, oxygen, and a sulfur atom. In one embodiment, the heteroaryl ring contains from 1 to about 2 scoops of 4 heteroatoms in the backbone of the ring. When the heteroaryl ring contains a nitrogen or sulfur atom in the backbone of the ring, the nitrogen or sulfur atom may be oxidized. The term "heteroaryl" also refers to a polycyclic ring 12 200848019 ring in which one heteroaryl ring system is fused to an aryl ring. The heteroaryl ring can be provided via a structure which provides the heterocyclic ring formed. A chemically stable heteroatom or carbon atom is attached to the aryl ring. In one embodiment, the heteroaryl ring comprises a polycyclic ring system having from 1 to 5 rings. 5 various heteroaryl groups are in the art Known and include, without limitation, a ring containing oxygen, a ring containing nitrogen, a ring containing sulfur, a ring containing mixed heteroatoms, a fused ring containing a hetero atom, and combinations thereof, etc. Heteroaryl Examples include, but are not limited to, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, morphine, pyrimidinyl, pyridinyl, tris-10, and sulfhydryl groups ( Azepinyl), thienyl, dithi〇lyl, oxythiol, oxazolyl, thiazolyl, oxadiazolyl, oxatriazole, oxepinyl, thiazepine (thiepinyl), diazepyl, benzofuranyl, thi〇napthene, sulfhydryl Benzoazolyl, purindinyl, piperac pyrrolyl, 15 isodecyl, hydrazine, benzoxazolyl, porphyrinyl, isoindolyl, benzoindole (benz〇diazonyl), naphthylridinyl, benzo σ thiophene, t π pyrid〇pyridinyi, π 丫唆 丫唆 (acridinyi), carbazolyl, and fluorenyl ring. The term "substituted heterocyclic ring" and, substituted hetero 20 aryl" as used herein, refers to a heterocyclic or heteroaryl group having one or more substituents including: i, CN , OH, oxime 02, amine, alkyl, cycloalkyl, alkenyl 'alkynyl, (^ to 匕perfluoroalkyl, 〇1 to (:3 perfluoroalkoxy, alkoxy) aryloxy a group comprising _〇_(CjCi 〇 )) or each ❿ to ^. a substituted alkoxy group, including -CCKGSCw alkyl) or 13 200848019 -CO-(C^C1() substituted The alkylcarbonyl group of the alkyl group, including the alkyl group of -C00_(Cd Cio alkyl) or -COOJCiSCw substituted alkyl), -C(NH2)=N-〇H, _S02-(CiC1G alkyl) , -S02-(CdC1G substituted alkyl), -O-CH2-aryl An alkoxy group, an arylthio group, an aryl group, an aryl or heteroaryl group 5, the group may optionally be substituted. A substituted heterocyclic or heteroaryl group may have 1, 2, 3, or 4 substituents. Such compounds may comprise tautomeric forms of the structures provided herein, which are characterized by the biological activity of the structures drawn. Alternatively, the compound may be used in the form of a salt derived from a pharmaceutically or physiologically acceptable acid, base, alkali metal or alkaline earth metal. Pharmaceutically acceptable salts can be formed from organic and inorganic acids including, for example, acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid , malic acid, citric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthenesulfonic acid, 15 benzoic acid, toluenesulfonic acid, camphorsulfonic acid, and the same known Accepted acid. Salts may also be formed from inorganic bases, desirably alkali metal salts including, for example, sodium, lithium, or potassium, and formed from organic bases such as, for example, ammonium salts, mono-, mono-, and trimethylammonium, single , di, and triethylammonium, mono-, di-, and tripropylammonium (iso- and n-butyl), ethyl dimethylammonium, benzyl dimethyl ketone, cyclohexyl decyl ammonium, benzyl ammonium, Diphenylmethylammonium, base bite, moffin rust (m〇rph〇, linumi), pyrrolidine rust (pyrr〇lidini·), hexahydropyrazine, ι_methyl determinate 4_ethyl Morpholinoin, 1_isopropylpyrrolidinium, 1,4-dimethylhexahydrofuran rust, ^butyl group, 2 methyl group, 丨·ethyl j•methyl bite镔, mono, di, and triethanolammonium, ethyl diethanolammonium, n-butyl 14 200848019 monoethanolammonium, cis (hydroxymethyl)methylammonium, phenyl monoethanolammonium, and the like. Physiologically acceptable alkali metal salts and alkaline earth metal salts may include, without limitation, sodium, potassium, calcium, and magnesium salts in the form of esters, and amine methyl esters, and other compounds, which may be esters. , amine methyl esters and other common 'prodrugs' forms exist which, when administered in this form, are equivalent to conversion into active moieties in vivo. In one embodiment, the prodrugs are esters. In the examples, the prodrugs are amine methyl esters. See, 10 For example: B. Testa and J. Caldwell, "Prodrugs Revisited: The ''Ad Hoc" Approach as a Complement to Ligand Design", Medicinal Research Reviews, 16(3): 233-241, ed.? John Wiley & Sons (1996). The compounds discussed herein also contain "metabolites", which are unique by 15 cells or individual processing compounds. product. Desirably, the metabolite is formed in vivo. The compounds described herein can be prepared using only the reagents and procedures known in the art. However, a combination of such agents and steps according to the present inventors is a compound of the following structure wherein RrR7 is as defined above. H Η

15 200848019 In summary, the compounds of formula i are prepared by combining an arylsulfonyl (1) group with a monoamine (2) under various conditions to form an arylsulfonamide (3). The arylsulfonamide can be combined with a cyanopyrrole to form a compound of formula I. See, Route 1.

Route 1 The first step comprises reacting an amine, such as HNR1R2, with an arylsulfonyl group having the structure wherein R 3 - R 6 are as defined above, and LG is selected from Cl, Br, F, or a leaving group of imidazole, and D system 10 a halogen or sulfonate. In one embodiment, D is a halogen. In a further embodiment, D is Br. In another example, the D is a sulfonate.

15 A sulfonamide prepared using a monoamine such as HNRiR^, Ri and R2 as defined above. In one embodiment, greater than one equivalent of amine is used. In another embodiment, about 10 equivalents of amine are used. The reaction is also desirably carried out in the presence of a base. A variety of bases can be selected for use in this reaction and can be selected by a person familiar with the art. Examples of bases include, inter alia: 16 200848019 Sodium carbonate, carbonic acid clocks, gasification hydrazine, fluorinated clocks, or acid clocks. The reaction is typically carried out in dichloromethane, although other solvents may be selected by the skilled artisan. By this, a sulfonamide having the following structure is prepared, wherein Ri-R6 and D are as defined above. 5

D^ (3) Sulfonamide is coupled to a pyrrole containing a leaving group. In one embodiment, the pyrrole comprising a leaving group is a pyrrolonitrile containing a leaving group. In a further example, the pyrrole comprising a leaving group is a boronic acid (5) having a structure of 10 or less, wherein R7 is as defined above. In another example, the pyrrole comprising a leaving group is a tin derivative of boric acid (5) having the structure: wherein R7 is an "alkyl" as defined herein.

Burning base

Η

OH (5) In a further example, a pyrrole comprising a leaving group can be prepared from lithium diisopropylamide, a trialkyl monoborate, and a mouth ratio (4) having the following structure, wherein the R7 system As defined above. A variety of acid-cutting triesters can be selected for coupling by a person skilled in the art. Specific examples of the trialkyl borate include, without limitation, trimethyl borate, triethyl borate, 17 15 200848019 or triisopropyl acid monoester. v

N<V R7 (4). It is desirable to implement it in the presence of a catalyst. There are various palladium catalysts available in the art which are useful in coupling and include, but are not limited to: tetrakis(triphenylphosphine)! Tetrakis (triphenylphosphine) palladium (0) or palladium dibenzylidene acetone in the presence of tributylphosphine (Fu et al, J. Am. Chem. Soc., 2000) , 122, 4020), and the catalysts/catalyst system described in Hartwig et al., J. 〇rg. 10 Chem. 2002, 67, 5553. Coupling also includes a test and can be chosen by a person familiar with the art. Bases can be used without limitation: sodium carbonate, potassium carbonate, cesium fluoride, potassium fluoride, and potassium phosphate. Likewise, a wide variety of solvents can be selected for coupling and include, without limitation: tetrahydrofuran 15 (THF), dimethoxyethane (DME), dioxane, ethanol, water, toluene, or Is one of its combinations. Depending on the reactivity of the coupling partner and the reagent, the reaction is carried out at a boiling point up to the solvent, or it can be accelerated under microwave irradiation, which can be easily determined by a person skilled in the art if necessary. 20 In each embodiment, the compound of formula I is prepared as described in Route 2 by reacting bromo-methanesulfonyl (1) with amine (2) to produce Sulfaguanamine (3), which in turn is coupled to a pyrrole boronic acid (5) or a pyrrole compound prepared using pyrrole (4). 18 200848019

Route 2 also prepares a pharmaceutical composition comprising one or more of the compounds described herein and a pharmaceutically acceptable carrier or excipient. In one embodiment, the method of treatment comprises administering a pharmaceutically effective amount of one or more compounds as described herein as a progesterone receptor modulator to a mammal. The compound may be combined with one or more pharmaceutically acceptable carriers or excipients such as solvents, diluents and the like. Suitably, the compounds are formulated for delivery to a body via any suitable route, including, for example, transdermal, mucosal (intranasal, buccal, vaginal), oral, non-menstrual Intestines. A variety of suitable delivery devices can be used in such delivery routes and include, without limitation, in particular: lozenges, caplets, capsules, tablets, dispersible powders, granules, suspensions, injectables Solutions, transdermal patches, topical creams or gels, and vaginal rings. 15 In the preparation of the compositions described herein, the compounds may be combined with, in particular, one or more of a solid carrier, a liquid carrier, an adjuvant, a suspending agent, a syrup, and a medicinal agent, selected as the active ingredient. The nature and specific form of administration desired. Solid carriers include, without limitation, starch, lactose, dicalcium phosphate, 20 microcrystalline cellulose sucrose, and kaolin. Liquid carriers include, without limitation: sterile water, dimethyl hydrazine (DMS0), 19 200848019 polyethylene glycol, nonionic surfactants, and edible oils such as [corn peanuts and sesame oil. 5 10 15 20 Adjuvants can include, without limitation: flavoring agents, coloring agents, preservation 1, and antioxidants, such as: vitamin E, ascorbic acid, butylated hydroxymethyl benzoate (ΒΗΤ and butyl hydroxyanisole (ΒΗΑ). In embodiments, the compound may be combined with a suspending agent, including from about 0.05 to about 5% of a suspending agent. In another embodiment, the compound may be combined with a sugar syrup containing, for example, from about 10 to about 50°. In a further embodiment, the composition may be combined with a brew containing, for example, large, spooned 20 to large, 45 G/. ethanol, and the like. The field formulation is used for oral delivery. The compound can be a d-fixing agent, a lumbar elliptic bond, a _, a dispersible powder, a granule, or a suspension: in the form of "easy preparation and administration, a special phonopharmaceutical composition is a solid composition" In particular, (4) and hard = liquid capsules, and fillings and mouthpieces may also be administered in a solution, suspension, or knife solution in a non-intestinal or intraperitoneal manner. Such pharmaceutical preparations may contain, for example, Approximately 25 to approximately 9 ()% of the Desirably, the pharmaceutical preparation contains about 5% and 6% by weight of the compound, which is administered in a solution or suspension, whereby the compound is administered. Is free of your salt base or pharmaceutically acceptable salt, and is suitable for surfactants, such as: water mixed with propyl cellulose. In another embodiment, containing compounds The solution or suspension 20 200848019 may contain from about 0.05 to about 5% of a suspending agent in an isotonic medium. In one additional embodiment, the compound is administered in a dispersion which is specifically formulated for dispensing. Prepared in glycerol (glyCer®) in liquid, liquid, polyethylene glycol, and mixtures thereof, etc. 5 Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and solutions or dispersions without ii injectable solutions A sterile powder of an expedient preparation. In all cases, it must be in a sterile form and must be liquid to the extent that it is easy to inject. It must be stable under the conditions of manufacture and storage and must The contamination of microorganisms, such as bacteria and fungi, can be preserved. The carrier used in the injectable form can be a solvent or dispersion medium containing, for example, water, ethanol (eg glycerol, propylene glycol) And a liquid polyethylene glycol), a suitable mixture thereof, and a vegetable oil. The compound can also be administered via a vaginal ring. Suitably, the use of the vaginal ring 15 is arranged for a period of time in which the compound is administered, including 28 days. However, the vaginal ring can be inserted for a longer or shorter period of time. See, U.S. Patent Nos. 5,972,372; 6,126,958; and 6,125,85G, which are hereby incorporated by reference. Material, about the vaginal ring formula that can be used. 20 Compounds can also be delivered via a transdermal patch. Suitably, the use of the patch is scheduled to be the length of the desired period, including the period of the day. However, the patch can be maintained in place for a longer or shorter period of time. Compounds can be used in the following methods: contraception, hormone supplementation therapy 21 200848019, and treatment and/or prevention of benign & malignant neoplastic diseases; cycle-related symptoms; fibroids, including uterine fibroids; fibroids; Cystic footprint syndrome; endometrial tissue ectopic; benign prostate hypertrophy; endometrial cancer and adenocarcinoma, nest, breast, colon, prostate, pituitary, meninges 5 tumors sigh _ hormone Dependent miscellaneous; machine-induced uterine bleeding; symptoms of premenstrual syndrome and premenstrual discomfort; and induction of menstruation. Additional uses of the progesterone receptor modulators include stimulating food intake and synchronization of estrus in livestock. In one embodiment, the neoplastic disease is hormone dependent. 1 〇 The term 'cycle-related symptoms' refers to psychological symptoms associated with a woman's menstrual cycle (eg, mood changes, irritability, anxiety, inattention, or loss of libido) and physical symptoms ( For example: dysmenorrhea, breast tenderness, bulging, fatigue, or food cravings. Cycle-related symptoms include, but are not limited to, dysmenorrhea and moderate to severe cycle-related symptoms. 15 ▲ When used for this purpose, 'these compounds can be combined with other preparations' and combined with each other. Such preparations include, without limitation,, in particular, vapours, anti-page hormones, hormones, anti-hormone, and selective hormone receptor modulators (SERMS). Lutein can include, without limitation: tanaPr〇get, levonorgestrel, n〇rgestrel, desogestrel, 3- 3-ketodesogestrel, norethindrone, gestodene, blocknosyl acetate, norgestimate, osaterone, acetaminophen acetate Progesterone (Cypr〇teiOne acetate), trimegestone (trimegestone), dienogestin (dienogest), trospireone 22 200848019 (drospirenone), omnigestrol ig (nomegestrol), or (17-deacetylated 醯Base) Norgestimate. Estrogen can include, without limitation, ethinyl estradiol. The compounds described herein can be combined with one or more of these formulations, delivered concomitantly with one or more of these formulations, delivered prior to one or more such formulations, or one or more of these Delivered after formulation. A patient or individual to be treated is a mammalian individual, and typically a female. Desirably, the individual is a human being. However, as used herein, a female property includes non-human mammals such as cattle or baboons, horses, worms, bred animals, and the like. The effective dose of the compound can vary depending on the particular compound employed, the mode of administration, and the severity of the condition being treated. However, in general, a daily dose of from about 〇5 to about 500 mg/kg of animal body weight is from about 1 to about 400 mg/kg, from about 5 to about 300 mg/kg, from about 10 to about 250 mg. /kg, about 50 to about 200 mg/kg, or about 1 to 15 to 150 mg/kg of the compound to be administered will give satisfactory results. For most large mammals, the total dose per dose is from about 1 to 1 mg. In one embodiment, the total daily dose is from about 2 to 80 mg. This dose regimen can be adjusted to provide the optimal therapeutic response. For example, several separate doses may be administered daily or the dose may be proportionally decreased as indicated by the severity of the treatment condition. As mentioned previously, the compound can be administered via a vaginal ring. In one embodiment, the ring system is inserted into the vagina and it is maintained in a suitable volume for 3 weeks. During the fourth week, the vaginal ring was removed and the lunar surface occurred. In the following week, insert a new ring that will be worn for another 3 weeks. 23 200848019 The time until the next cycle has arrived. In another embodiment, the vaginal ring is inserted weekly and replaced for 3 weeks in a row. Then, for the next week without a ring, a new ring system was inserted to start a new regimen. In still another embodiment, the vaginal ring system is inserted for a longer or shorter period of time 5 . In addition, the previously mentioned transdermal patches are applied to the skin via a suitable adhesive which is maintained in place for at least one week. In one embodiment, the transdermal patch is maintained in place for a week and a weekly replacement for a total of 3 weeks. In another embodiment, the transdermal patch is held in place for 2 weeks. In one additional embodiment, the transdermal patch is maintained in place for 3 weeks. There was no patch and menstruation occurred during the fourth week. The next week, apply a new patch to be applied to start a new regimen. In still another embodiment, the patch is maintained in place for a longer or shorter period of time. 15 When used in contraception, the method typically involves delivering a daily dosage unit containing a compound for 28 consecutive days to a female of the delivery age. Desirably, the method comprises delivering the compound for a continuous period of 21 to 27 days, followed by no effective amount of the compound or no delivery compound for 1 to 7 consecutive days. Alternatively, the delivery of an effective amount of the compound to the individual for a period of from 1 to 20 days can involve the delivery of a daily dosage unit of from 1 to 7 days of a second phase of a pharmaceutically acceptable placebo. Optionally, no placebo was administered during this period of 'placebo'. The compounds can be selectively administered in combination with a lutein, anti-lutein, estrogen, or a combination thereof, etc. 24 24 200848019 In another embodiment, the method comprises delivering a compound for 21 consecutive days, followed by no delivery An effective amount of the compound for 7 days. Optionally, during these 7-day periods, a second phase of 7 oral dosage units of the oral and pharmaceutically acceptable placebo can be delivered. The compounds can be administered in combination with a lutein, anti-lutein, estrogen, antiestrogens, SERM or a combination thereof. In a further embodiment, the method comprises delivering the compound for 23 consecutive days, followed by no delivery of an effective amount of the compound for 5 days. Alternatively, during these 5 day periods, a second phase of oral administration and 10 pharmaceutically acceptable placebo doses of 5 daily dosage units can be delivered. The compounds can be selectively administered in combination with a lutein, anti-lutein, estrogen, antiestrogens, SERM or a combination thereof. In still another embodiment, the method comprises administering a compound for 25 consecutive days, followed by 3 days of delivery of an effective amount of the compound. Alternatively, during these 3 day periods, an oral and pharmaceutically acceptable placebo of 3 daily dosage units of the second stage can be delivered. The compounds may be optionally administered in combination with a lutein, anti-lutein, estrogen, antiestrogens, SERM or a combination thereof. In still another embodiment, the method comprises delivering a compound of the formula for 27 consecutive days, followed by no delivery of an effective amount of the compound for 1 day. Optionally, a second phase of one oral and pharmaceutically acceptable placebo dosage unit can be delivered. The compounds can be selectively administered in combination with a lutein, anti-lutein, estrogen, antiestrogens, SERM or a combination thereof. 25 200848019 In another embodiment, a method of contraception includes administering a female to a delivery age for 28 consecutive days: (the first phase of 14 to 24 phase fields is about 35 to about 1 〇〇pg of left-handedness) a progestational agent per amphibious dosage unit of the progesterone activity of the block of progesterone; (b) - a daily dose unit of from 1 to n of a compound of the fifth embodiment described herein, in the range of from about 2 to about 50 a maternal dose of mg; and (c) optionally, a daily dose unit of one of the third stages of oral and pharmaceutically acceptable placebo for the remainder of 28 consecutive days in which no anti-lutein is administered, Lutein or estrogen; wherein the total daily dosage unit of the first, second, and third stages is equal to 28. 10 In still another embodiment, a method of contraception includes administering a female to a delivery age 28 consecutive days: (a) 14 to 24 daily dosage units of a compound as described herein in the first stage; 1) a daily dose of 1 to 11 of a second phase of primary anti-lutein Unit; and (c) selectively, One of the third stages of oral and pharmaceutically acceptable solubilization of 15 doses of the daily dosage unit lasts for the remainder of 28 consecutive days, wherein no drug is administered against the voxel, lutein, estrogen, antiestrogens or SERM; The total daily dosage unit for the first, second, and third stages is equal to 28. In still another embodiment, a method of contraception and a 28-day continuous period of administration comprising a female to a delivery age are provided: (a) - 14 to 24 of the first 20 stages correspond to between about 35 and about 10 a progestational agent per dose unit of the progestational activity of xanthonorgestrel; (b) - a daily dose unit of one to eleven of a compound described herein in the second stage, approximately a daily dose of 2 to 50 mg; and (c) optionally, a second dose of one or more of the oral and pharmaceutically acceptable placebos of the daily dose of 26 200848019 - 5 10 for 28 consecutive days The remaining time, in which no anti-lutein, lutein or estrogen is administered; wherein the total daily dosage unit of the first, second and third stages is equal to 28. In another embodiment, a method of providing contraception and a female comprising administering to a childbirth are consecutive for 28 days: (a) a first stage: as illustrated herein - 14 to 24 of each compound Daily dosage unit; (9) - the second phase of the daily dose unit of m anti-lutein; and (4) the third stage of the "daily dose unit of oral and pharmaceutically acceptable placebo" The remaining time of 28 consecutive days, in which no anti-lutein, lutein, estrogen, anti-emin or serm were administered; wherein the total daily dosage unit of the first, second and third stages was equal to Μ. Kits or packages designed to make (4) (iv) formulations for use in the regimen described herein are also provided. Suitably, the kit contains _ or a plurality of compounds as described herein. 15 Advantageously, for use in a kit, the compound is formulated for the desired delivery of it and it彳i. By way of example (d), the compound can be formulated for oral delivery, parenteral delivery, vaginal ring, transdermal delivery, or mucosal delivery, as discussed in detail above. The kit preferably contains one of the daily doses arranged in the order in which it is to be taken (e.g., a blister pack 20). In this paper, it is preferred to fix each of the pharmacy remnants in each scale. It is also understood that the illustrated daily dose units are given in the order stated in the explanation (4), and the same stage is followed by the selected step 27 200848019, including any compliance with the second and third stage methods, green containing Correction _ = Qian Sheng is also better. It is preferable to package the indicators of each package or set of days of the previous day, for example: two standard two = cover d $ degree dispenser, or other packages known in the art. The regimen can be adjusted to provide the best therapeutic response. For example, the number of _ doses of each saki can be transferred to the day or the dose can be increased or decreased by the amount of material. In the description of this article, about - each dose unit is also

Units that can be administered during the course of each day of the expected cycle can be included. J 15 20 In the oral target case, the design kit is used for a period of 28 days and is used daily for oral administration and for organizing to indicate each day of the 28-day cycle. A combination of (4)-single-mouth s or a combination of oral formulations. Desirably, each set will be included in the number of days indicated in each poem (4), and the desired daily dose of each combination. An effective amount of the compound is 21 to 27 daily dosage units, optionally selected as a placebo and other 1 to 7 daily dosage units including, for example, suitable for Wei Ming. In another example, the kit is designed to be administered weekly or monthly via a vaginal ring for a period of 28 days. Suitably, the kit contains the individual vaginal rings required for the monthly cycle, i.e., (1), individual packaging of 28 200848019, and other suitable components including, for example, instructions for use. In a further embodiment, the design kit is configured for weekly or monthly administration via a percutaneous patch for a period of 28 days. Suitably, the five sets of sets contain each of the patches required for the monthly cycle, i.e., one to three, individual packages, and other suitable components including, for example, instructions for use. In yet another embodiment, the kit is designed to provide parenteral delivery of the compound. This set is typically designed for delivery at home and can include injection needles, syringes, and other suitable packaging and instructions for use. In still another embodiment, the kit contains a compound formulated in a gel or a poorly-preserved formula. Alternatively, the kit can include a suitable package, such as: a tube or other container, an applicator, and/or instructions for use. In a further embodiment, the kit comprises (a) - a first phase of 15 14 to 21 equivalents of a daily dosage unit equivalent to about 35 to about 150 pg of levonorgestrel progestational activity Pregnancy agent; (b) - 1 to 11 daily dosage units of a compound described herein in the second stage; and (c) one of the third stages of oral and pharmaceutically acceptable placebo For each dose unit; the total number of 20 daily dose units for the first, second, and third phases is equal to 28. In yet another embodiment, the 'set of groups contains (a) - the first stage of the 14 to 21 daily dosage units of a compound described herein; (b) the second stage of the primary anti-luteum 1 to 11 daily dosage units of the prime compound; and (c) one of the third stages of oral and pharmaceutically acceptable An 29 200848019, agent = daily dosage unit; The total number of daily dose units in the second phase and the self is equal to 28. The following examples are merely illustrative and are not intended to be a limitation of the invention. EXAMPLES Example 1 : Preparation of Amine 4_(5·Cyano_1_methyl·1Η_ 口比咯_2_yl)·Ν_Methylbenzenesulfonate

10 Step 1: 4 & 1 > Preparation of Odor-N-methylbenzenesulfonamide

General procedure for the preparation of sulfonamides from sarcophagus and chlorinated chlorine A 4 · bromo sulfoxime (0·40 g, 1.56 mmol) and methylamine (10 mL, 33% in ethanol) are stirred in a sealed tube for a duration of time. 16 hours. The reaction mixture was concentrated in vacuo on a Celite® reagent. The crude product was purified by a 15 ISC 〇 chromatograph (Redise PTM column, sulphur dioxide, gradient 0-3% ethyl acetate-dichloromethane) to prepare 4-bromo-methylbenzenesulfonamide (( U1 g, 28%) ° MS (ESI) m/z 250. High performance liquid chromatography (hplC) purity 100.0% at 210-370 nm, 7.4 min·; Xterra® RP18 column, 3·5μ, 150 χ 4·6 mm column '1.2 mL/min., 85/15-5/95 (ammonium formate buffer 20 ρΗ=3·5/acetonitrile (ACN) + MeOH) for 1 minute, for 4 minutes. General Procedure for the Coupling of Brominated Aryl and Boronic Acids Step 2 : 30 200848019 4-Bromo-N-methylbenzenesulfonamide (100 mg, 0.40 mmol), 5-cyano-1-methyl-1H Bis-2-ylboronic acid (72 mg, 0·48 mmol), potassium fluoride (76 mg, 1.3 mmol), and bis(diphenylideneacetone) dipalladium (O)) (10 mg, 0.01 5 mmol) was placed in an oven-dried flask in nitrogen and dry THF (1.0 mL) was added. Tri-tert-butylphosphine (60 pL, 0.02 mmo) was added. Equipped with 10 wt% of hexane and stirred for 16 hours. The reaction mixture was passed through cerium oxide. Filtration and rinsing with ethyl acetate. The solvent was concentrated in vacuo to give a crude material. The crude product was pre-absorbed on Celite® 10 and passed through Isco chromatography (RedisepTM column, cerium oxide). Purified with a gradient of 5-50% ethyl acetate in hexanes to provide 4-(5-cyano-1-indolyl-1H-pyrrol-2-yl)-N-methylbenzenesulfonamide ( 28 mg, 25%) MS (ESI) m/z 275. HPLC purity at 210-370 nm 100.0 〇/〇, 9.0 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm 15 column , 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) lasted for 10 minutes for 4 minutes. Example 2: 4-(5-murine-1 -Methyl)-N,N-dimethylbenzenesulfonamide

Step 1: In a manner similar to General Procedure A, 4-bromobenzenesulfonate (0.4 g, 1.56 mmol) was stirred with dimethylamine (10 mL, 33% in ethanol) for 16 hours. 4-Bromo-indole, indole dimethyl sulfonamide (0.11 g) was prepared after purification. MS (ESI) m/z 264. HPLC purity at 210-370 nm 31 200848019 100.0%, 8.3 min·; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 85/15_5/95 (ammonium molybdate buffer) The agent pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Step 2: 4-bromo-N,N-dimethyl 5-phenylsulfonamide (105 mg, 0.40 mmol), 5-cyano-1-indenyl-indole-n^π in a manner similar to the general procedure B Each-2-pyrhenic acid (72 mg, 0.48 mmol), fluorinated clock (76 mg, 1.3 mmol), and ginseng (diphenylmethyleneacetone) di I bar (〇) (10 mg, 0.01 mmol) Place in an oven-dried flask in nitrogen and add dry THF (1. 〇 mL). Tri-tert-butylphosphine (60 μί, 0.02 mmol, with 10 10 wt% of hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethylbenzenesulfonamide (30 mg, 26%) was prepared after purification. HRMS: Analytical value for C14H15N302S + H+, 290.09577; (ESI, [M+H]+) found, 290.0964. HPLC purity at 210-370 nm 100.0%, 9.8 min.; Xterra® RP18 column, 3·5 μ column, 150 X 15 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (antic acid) Ammonium buffer pH = 3.5 / ACN + MeOH) was maintained for 10 minutes for 10 minutes. Example 3: Preparation of 4-(5-cyano-1-methyl-1H.pyrrol-2-yl)-N-ethylbenzenesulfonamide

20 Step 1: Using the general procedure A, 4-bromobenzenesulfonyl chloride (0.40 g, 1.56 mmol) and ethylamine (5 mL, [2·0 Μ], 10 mmol) were mixed for 16 hours. 4-Bromo-N-ethylbenzenesulfonamide (〇·11 g) was prepared after purification. MS (ESI) m/z 264. HPLC purity at 210-370 nm 100.0%, 8·1 32 200848019 min.; Xterra® RP18 column, 3·5μ, 150 χ 4·6 mm column, 1.2 mL/min·, 85/15-5/ 95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. Step 2: 4-bromo-N-ethylbenzene 5 sulfonamide (105 mg, 0.40 mmol), 5-cyano-1_methyl-1H-pyrrole-2-yl, in a similar manner to the general procedure B Benzolic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and ginseng (diphenylarbenium) 1 I bar (0) (10 mg, 0.01 mmol) Nitrogen was placed in an oven-dried flask and dry THF (1.0 mL) was added. Tri-tert-butylphosphine (60 μί, 0.02 mmo with 10 wt% of hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-ethylbenzenesulfonamide (15 mg, 13%) was prepared after purification. MS (ESI) m/z 289. HPLC purity at 210-370 nm 100.0%, 9.6 min.; Xteira® RP18 column, 3·5μ, 150 χ 4·6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate) The buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes and maintained for 4 minutes and 15 minutes. Example 4: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propylbenzenesulfonamide

Step 1 · General procedure for the formation of sulfonamide from sulfonium chloride C 20 Dissolve 4-bromobenzenesulfonyl chloride (0.40 g, 1.5 mmol) in a sealed tube with propylamine (0.32 mL, 3.90 mmol) ) in dichloromethane (5 mL). The mixture was stirred for 16 hours and vacuum concentrated on a Celite® reagent. The crude product was purified by Isco chromatography (RedisepTM column, cerium oxide, 33 200848019 gradient 0-3% ethyl acetate-dichloromethane) to prepare 4·bromo-N-propylbenzenesulfonamide (0.12 g, 28%). MS (ESI) m/z 278. HPLC purity at 210-370 nm 100.0%, 8.8 min.; Xterra8 RP18 column, 3·5μ, 150 χ 4.6 mm column, 1·2 mL/min·, 85/15-5/95 (ammonium formate buffer) Agent 5 pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2 ·According to the procedure B ' 4-> odor-N-propyl benzene-branched amine (111 mg, 0·40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-yl Boric acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and ginseng (diphenylmethyleneacetone) dipalladium (0) (10 mg, 〇.〇1 mm〇l) in nitrogen It was placed in an oven 10 dried flask and dried THF (1.0 mL) was added. Tri-tert-butylphosphine (60 μί, 0.02 mmol, 10 wt% in hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1s-pyrrol-2-yl)-N-propylbenzenesulfonamide (21 mg, 17°/〇) was prepared after purification. MS (ESI) m/z 303. HPLC purity at 210-370 nm 100.0%, 10.2 min.; Xterra® 15 RP18 column, 3·5μ, i5〇χ 4 6 mm column, 1.2 mL/min·, 85/15-5/95 (antic acid) The ammonium buffer pH = 3 5 / AcN + MeOH) was maintained for 4 minutes for 10 minutes. Example 5: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)isopropylbenzenesulfonamide

Step 1: According to the general procedure C, 4-bromobenzenesulfonium chloride (〇·40 g, 1.56 mmol) and isopropylamine (〇·33 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL). 16 hours. 4-Bromo-N-isopropylbenzenesulfonamide (〇·12 g, 34 200848019 28%) was prepared after purification. MS (ESI) m/z 278. HPLC purity at 210-370 nm 100.0%, 8.7 min.; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1·2 mL/min. '85/15-5/95 (ammonium formate) Buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 5 Step 2: According to the general procedure B, 4-bromo-N-isopropylbenzenesulfonamide (111 mg, 0·40 mmol), 5-cyano-1-methyl-1H_phenpirol-2- Boronic acid (72 mg, 0·48 mmol), fluorination (76 mg, 1.3 mmol), and ginseng (diphenylmethyleneacetone) di-bar (〇) (10 mg, 0.01 mmol) Nitrogen was placed in an oven-dried flask and dry THF (1.0 mL) was added. Tri- 10th tributylphosphine (60 μΐ^, 0. 02 mmol, 10 wt% in hexane) was added and the reaction was stirred for 16 hours. 4·(5-Cyano-1-methyl-1Η·pyrrol-2-yl)-N-isopropylbenzenesulfonamide (15 mg, 12%) was prepared after purification. MS (ESI) m/z 303. HPLC purity at 210-370 nm 100.0%, 10.1 min.; Xterra® RP18 column '3·5μ, 15〇χ 4·6 mm column, 1.2 mL/min., 15 85/15-5/95 ( Ammonic acid ammonium buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 6: Preparation of 4-(5-cyano-1-methyl-ih-pyrrol-2-yl)-N-isobutylbenzenesulfonamide

Step 1 ·· Based on the general procedure C, 4-bromobenzenesulfonate (0.40 g, 1.56 mmol) and isobutylamine (〇·39 mL, 3.90 mmol) were stirred with dry dichloromethane (5 mL) It lasted for 16 hours. 4-Bromo-N-isobutylbenzenesulfonamide (0.12 g, 28 〇/〇) was prepared after purification. Ms (ESI) m/z 292. HPLC purity at 210-370 nm 35 200848019, 100.0%, 9·4 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min·, 85/15_5/95 (ammonium formate) Buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-isobutylbenzenesulfonamide (117 5 mg, 0.40 mmol), 5·cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 Mg, 0.48 mmol), fluorinated clock (76 mg, 1.3 mmol), and ginseng (diphenylmethyleneacetone) gemini (〇) (10 mg, 0.01 mmol) were placed in an oven and dried in an oven. Dry THF (1.0 mL) was added to the flask. The addition of tri-tertiary phosphine (60 μί, 0.02 mmol, with 10 wt% of hexane) and the addition of the reaction 10 should last for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-isobutylbenzenesulfonamide (11 mg, 9%) was prepared after purification. MS (ESI) m/z 317. HPLC purity at 210-370 nm, 100.0%, 10.8 min.; Xterra® RP18 column, 3.5 μm, 150 x 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes and 15 minutes. Example 7: Preparation of 4-(5-cyano-1-indenyl-1H-pyrrol-2-yl)-N-ethyl-N-methylbenzenesulfonamide

Step 1: According to the general procedure C, 4-bromobenzenesulfonium chloride (0.40 g, 1.56 20 mmol) and N-ethyl-N-methylamine (0.33 mL, 3.90 mmol) in dry di-methane (5 mL) Stirring together for 16 hours. 4-Bromo-N-ethyl-N-methylbenzenesulfonamide (0.12 g, 28%) was prepared after purification. MS (ESI) m/z 278. HPLC purity at 210-370 nm 99.2%, 8.9 min· ; Xterra® RP18 36 200848019 column, 3·5μ, 150 x 4.6 mm column, 1·2 mL/min·, 85/15-5/95 ( The ammonium molybdate buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes over 10 minutes. Step 2: According to the general procedure B, 4-bromo-N-ethylmercaptobenzenesulfonamide (111 mg, 0.40 mmol), 5-cyanoberberyl-1H-pyrrol-2-ylboronic acid 5 (72 mg , 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and ginseng (diphenylmethyleneacetone) dipalladium (0) (10 mg, 0. 01 mmol) were placed in an oven and dried in an oven. The flask was also filled with dry THF (1.0 mL). Tri-tert-butylphosphine (6 〇 μί, 0.02 mmo was added to 1 〇 wt%) and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-10 ethyl-N-methylbenzenesulfonamide (17 mg, 14%) was prepared after purification. MS (ESI) m/z 303. HPLC purity at 210-370 nm 99.5%, 10.3 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 15 Example 8 Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethylbenzenesulfonamide

Step 1 ··············· Stirring took 16 hours. 4-Bromo-N,N-diethylbenzenesulfonamide (0.12 g) was prepared after purification. MS (ESI) m/z 293. HPLC purity at 210-1370 nm 99.2%, 9.4 min·; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium acid acrylate buffer) 37 200848019 pH=3.5/ACN+MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B ' 4-Mo-N,N-diethylbenzene ore (117 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid ( 72 mg, 〇·48 mmol), potassium fluoride (76 mg, 1.3 mmol), and ginseng (diphenylarbenium propionin 5 _) di Ib (0) (10 mg, 0·01 mmol) in nitrogen It was placed in an oven-dried flask and dry THF (1.0 mL) was added. Tri-tert-butylphosphine (60 μί, 0.02 mmol, 10 wt% in hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethylbenzenesulfonamide (27 mg, 21%) was prepared after purification. MS (ESI) m/z 10 317. HPLC purity at 210-370 nm 100·0%, 10.8 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate) Buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 9: Preparation of N-(t-butyl)-4-(5-cyano-1-indenyl-1H-pyrrol-2-yl) 15 benzenesulfonamide

Step 1: According to the general procedure C, 4-bromobenzenesulfonium chloride (0.40 g, 1.56 mmol) was stirred with tributylamine (0.41 mL, 3.90 mmol) in dry dichloromethane (5 mL). It lasted for 16 hours. 4-Bromo-N-(t-butyl)benzenesulfonamide 20 (0.12 g) was prepared after purification. MS (ESI) m/z 292. HPLC purity at 210-370 nm 100.0%, 9.2 min.; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium acid acrylate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 38 200848019 Step 2: 4-bromo-N-(t-butyl)benzenesulfonamide (117 mg, 0.40 mmol), 5-cyanomethyl-1H-pyrrol-2-ylboronic acid according to the general procedure B (72 mg, 0.48 mmol), potassium carbonate (76 mg, 1.3 mmol), and ginseng (diphenylmethyleneacetone) di Ib (0) (10 mg, 0.01 mmol) were placed in nitrogen in 5 Dry the flask in an oven and add dry THF (1.0 mL). Tri-tert-butylphosphine (60 μί, 0.02 mmol, with 10 wt% of hexane) was added and the reaction was stirred for 16 hours. N-(Tert-butyl)-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzenesulfonamide (19 mg, 15%) was prepared after purification. MS (ESI) m/z 317. HPLC purity at 210-370 nm 100.0%, 10.5 min.; 10 Xterra® RP18 column, 3.5μ, 150 x 4·6 mm column, 1·2 mL/min·, 85/15-5/ 95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) lasted 10 minutes for 4 minutes. Example 10: 1-Methyl-5-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-methylazurine (l-methyl-5-[4- Preparation of (pyrrolidin-l-15 ylsulfonyl)phenyl]-lH-pyrrole-2-carbonitrile)

Step 1: According to the general procedure C, 4-bromobenzenesulfonyl chloride (0.40 g, 1.56 mmol). Billion. Stirring (0.32 mL, 3.90 mmol) in dry methylene chloride (5 mL) was stirred for 16 h. 1-[(4-Bromophenyl)sulfonyl p-pyrrolidine 2? (0.12 g) was prepared after purification. HRMS: Analytical value of C1()H12BrN02S + H+, 289.98449; (ESI, [M+H]+) found, 289.9847. HPLC purity at 91-170 nm 99.1%, 8.9 min.; Xterra® RP18 column, 3·5μ, 150 χ 4·6 mm column, 1.2 mL/min., 85/15-5/95 (ant 39 200848019 Ammonium Phosphate Buffer pH=3.5/ACN+MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 1-[(4-bromophenyl)sulfonyl]pyrrolidine (116 mg, 0.40 mmol), 5-cyano-1-methyl-111-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), a fluorinated clock (76 mg, 1.3 mmol), and ginseng (diphenylmethylene-5-propanone) gemini) (〇) (10 mg, 0.01 mmol) were placed in nitrogen Dry the flask in an oven and add dry THF (1.0 mL). Tri-tert-butylphosphine (60 μΐ^, 0.02 mmo bl. with 1% wt%) was added and the reaction was allowed to proceed for 16 hours. 1-Methyl-5-[4 decyl _1 _ _ _ 醯 醯 )) phenyl]]-1H-pyrrole-2-carbonitrile (7 mg, 6%) was prepared after purification. HRMS: Analytical estimate for 10 C16H17N302S + H+, 316.11142; (ESI, [M+H]+) found value, 316.1114. HPLC purity at 210-370 nm 100.0%, 10.3 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium acid ester buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 15 Example 11: Preparation of 1-methyl-5-[4-(piperidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile

Step 1: According to the general procedure C, 4-bromobenzenesulfonium chloride (0.40 g, 1.56 mmol) and bottom bite (0.38 mL, 3.90 mmol) in dry dichloromethane (5 mL) 20 with stirring for 16 hour. 1-[(4-Bromophenyl)sulfonyl]piperidine (0.13 g) was prepared after purification. HRMS: Analytical estimate of CuH^BrNOj + H+, 304.00001; (ESI, [M+H]+) found, 304.0009. HPLC purity at 210-370 nm 99.2%, 9.8 min.; Xterra8 RP18 column, 3.5μ, 40 200848019 150 χ 4·6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate) Buffer pH = 3.5 / ACN + MeOH) for 1 minute and held for 4 minutes. Step 2: According to the general procedure B, 1-[(4-bromophenyl)sulfonyl]piperidine (121 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 5 〇_48 mmol), potassium fluoride (76 mg, 1.3 mmol), and ginseng (diphenylmethyleneacetone) dipalladium (〇) (10 mg, 〇·〇1 mmol) in nitrogen It was placed in an oven-dried flask and dried THF (1.0 mL) was added. Tri-tert-butylphosphine (60 μ!^, 0. 02 mmol, 10% by weight in hexane) was added and the reaction was stirred for 16 hours. 1-Methyl-5-[4-(piperidin-1-ylsulfonyl)phenyl]-1H-10pyrrole-2-carbonitrile (11 mg, 8%) was prepared after purification. MS (ESI) m/z 329. HPLC purity at 210-370 nm 100.0%, 11.1 min.; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 15 Example 12: Preparation of 1-methyl-5-[4-(morpholine-4-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile

Step 1: According to the general procedure C, 4-bromobenzenesulfonate (0.40 g, 1.56 mmol) and morpholine (〇·34 mL, 3.90 mmol) in dry dichloromethane (5 mL) Stir together for 16 hours. 4-[(4-Bromophenylsulfonyl)inoline (0.13 g, 28%) was prepared after purification. MS (ESI) m/z 306. 8.2 min. ; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1.2 mL/min., 85/15-5/95 (antacid recording buffer 41 200848019 pH=3.5/ACN+MeOH) 10 minutes, hold for 4 minutes. Step 2 · According to the general procedure B, 4-[(4-bromophenylsulfonyl) phenanthroline (122 mg, 0.40 mmol), 5-cyano-1-methyl- 1H-port ratio bromo-2-ylboronic acid (72 mg, 0.48 mmol), fluorinated clock (76 mg, 1.3 mmol), and ginseng (diphenylmethylene 5- phenylacetone) di Ib (0) (10 mg, 0.01 mmol) was placed in an oven-dried flask in nitrogen and dry THF (1.0 mL) was added. Tri-tert-butylphosphine (60 g, 0.02 mmol, 10 wt% in hexane) was added and stirred. The reaction was carried out for 16 hours. 1-Methyl-5-[4_(morpholine-4-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile (11 mg, 8%) was prepared after purification. MS 10 (ESI) m/z 331. HPLC purity at 210-370 nm 100.0%, 9.7 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85 /15-5/95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes over 10 minutes. Example 13 · 4-(5-Alkyl-1-methyl-1 phenyl-2-yl) Preparation of -N-cyclobutylphthalide yellow 15 decylamine

Step 1: According to the general procedure C, 4-bromobenzenesulfonium chloride (0.40 g, 1.56 mmol) and cyclobutylamine (0.33 mL, 3.90 mmol) were stirred in dry methane (5 mL) for 16 hours. . 4-Bromo-N-cyclobutylbenzenesulfonamide (0.13 g) 20 was prepared after purification. MS (ESI) m/z 290. HPLC purity at 210-370 nm 95.6%, 9.1 min·; Xterra® RP18 column, 3·5μ, 150 χ 4·6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate) Buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 42 200848019 Step 2: According to the general procedure B, 4-bromo-N-cyclobutylbenzenesulfonamide (117 mg, 0.40 mmol), 5-cyano-1-methyl-111-pyrrole-2-ylboronic acid ( 72 mg, 0·48 mmol), fluorinated | A (76 mg, 1.3 mmol), and ginseng (dibenzylideneacetone) di Ib (0) (10 mg, 0.01 mmol) were placed in nitrogen Dry in a 5 box dry flask and add dry THF (1.0 mL). Tri-tert-butylphosphine (60 μM, 0.02 mmol, 1% by weight of hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutylbenzenesulfonamide (20 mg, 16%) was prepared after purification. MS (ESI) m/z 315. HPLC purity at 210-370 nm 98.8%, 10.4 min.; Xterra® 10 RP18 column '3·5μ, 150 x 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium acid buffer) Agent pH = 3.5 / ACN + MeOH) for 10 minutes 'keep for 4 minutes. Example 14: Preparation of 4-(5-cyano-1.methyl-1H-pyrrol-2-yl)-N-cyclopropylbenzenesulfonamide

Step 1: According to the general procedure C, 4-bromobenzenesulfonium chloride (0.40 g, 1.56 mmol) was stirred with cyclopropylamine (0.27 mL, 3.90 mmol) in dry dichloromethane (5 mL). hour. 4-Bromocyclopropylbenzenesulfonamide (0.12 g) was prepared after purification. MS (ESI) m/z 276. HPLC purity at 210-370 20 nm, 100.0%, 8.4 min·; Xterra® RP18 column, 3.5μ, 150 χ 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer) The agent pH = 3.5 / ACN + MeOH) was maintained for 1 minute and held for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-cyclopropylbenzenesulfonamide (110 43 200848019 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid ( 72 mg, 0.48 mmol), fluorinated unloading (76 mg, 1.3 mmol), and ginseng (diphenylmethyleneacetone) two (0) (10 mg, 0. 01 mmol) were placed in nitrogen. Dry in an oven and add dry THF (1.0 mL). Tri-pentabutylphosphine (60 pL, 0.02 mmo in hexane 10 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)cyclopropyl benzenesulfonamide (34 mg, 28%) was prepared after purification. MS (ESI) m/z 301. HPLC purity at 210-370 nm 100·0〇/〇, 9.6 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 10 85/15-5/95 (Ammonic acid ammonium buffer pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. Example 15: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclohexylbenzenesulfonylamine

15 Step 1: According to the general procedure C, 4-bromobenzenesulfonium chloride (0.40 g, 1.56 mmol) and cyclohexylamine (〇·46 mL, 3.90 mmol) in dry di-methane (5 mL) 16 hours. 4-Bromo-N-cyclohexylbenzenesulfonamide (0.13 g) was prepared after purification. MS (ESI) m/z 318. HPLC purity at 210-370 nm 1 〇〇·〇〇/0, 10·0 min.; Xterra8 RP18 column, 3·5μ, 150 20 χ 4.6 mm column, ι·2 mL/min., 85/ 15-5/95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Step 2: According to the general procedure B, 4_bromo-indolecyclohexylbenzenesulfonamide (127 mg, 0.40 mmol), 5-cyano-1-methyl·1Η-pyrrol-2-ylboronic acid (72 mg, 44 200848019 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and ginseng (diphenylmethyleneacetone) dipalladium (0) (10 mg, 0.01 mmol) were placed in an oven-dried flask in nitrogen. Add dry THF (1.0 mL). The addition of tri-tert-butylphosphine (60 μί, 0.02 mmo in hexane 10 wt%) and stirring in the reverse 5 should last for 16 hours. 4·(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclohexylbenzenesulfonamide (2 mg, 1%) was prepared after purification. MS (ESI) m/z 343. HPLC purity at 210-1370 nm 99.1%, 11.3 min.; Xterra® RP18 column, 3.5 μm, 150 x 4.6 mm column, 1.2 mL/min., 85/15_5/95 (pH 馁 buffer pH) =3.5/ACN+MeOH) lasted 10 minutes and 10 minutes for 4 minutes. Example 16: Preparation of 4-(5-cyano-1_methyl·1Η_pyrrole-2-yl)-N-(2,2,2-trifluoroethyl)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromobenzenesulfonium chloride (0.40 g, 1.56 15 mmol) and 2,2,2-trifluoroethylamine (0.32 mL, 3.90 mmol) in dry dichloromethane (5 mL The mixture was stirred for 16 hours. 4-Bromo-N-(2,2,2-trifluoroethyl)benzenesulfonamide (0.13 g) was prepared after purification. MS (ESI) m/z 318. HPLC purity at 210-370 nm 100.0%, 8.7 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ant 20 ammonium amide Buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-(2,2,2-trifluoroethyl)benzenesulfonamide (127 mg, 0.40 mmol), 5-cyano-1-methyl-indole- Orallo--2- succinic acid (72 mg, 0. 48 mmol), potassium hydride (76 mg, 1.3 mmol), and ginseng (two 45 200848019 benzylidene propyl S) two (0) (10 Mg, 0.01 mmol) was placed in an oven-dried flask in nitrogen and dry THF (1.0 mL) was added. Tri-tert-butylphosphine (60 pL, 0.02 mmol, 1% wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrole 5 1yl)-indole-(2,2,2-trifluoroethyl) cuminamide (57 mg, 42%) after purification Preparation. MS (ESI) m/z 343. HPLC purity at 210-370 nm 97.2%, 10.1 min·; Xterra8 RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (antimonic acid buffer pH) =3.5/ACN+MeOH) lasted 10 minutes for 4 minutes. 1〇 Example 17: Preparation of 4-(5-cyano-1-methyl-1H.pyrrol-2-yl)-N-(cyclopropylmethyl)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromobenzenesulfonyl chloride (〇.4〇g, 1.56 mmol) and cyclopropylmethylamine (0.35 mL, 3.90 mmol) in dry methylene chloride 15 (5 mL) The mixing was carried out for 16 hours. 4-Bromo-N-(cyclopropylmethyl)benzene oxime Amine (0.12 g) was prepared after purification. MS (ESI) m/z 290. HPLC purity at 210-370 nm 100.0%, 9.0 min· ; Xterra® RP18 column, 3·5μ, 150 χ 4·6 mm column, 1·2 mL/min·, 85/15_5/95 (ammonium formate) Buffer pH 2/ACN + MeOH) was maintained for 10 minutes for 10 minutes. 2〇Step 2: According to the general procedure B, 4-bromo-N-(cyclopropylmethyl)benzenesulfonamide (116 mg, 0·40 mmol), 5-cyano-1-methyl-lH-u ratio _2_2_ quinine (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and ginseng (diphenylmethylene acetonate) two (0) (10 mg, 0.01 mmol) Nitrogen was placed in an oven-dried flask at 46 200848019 and dried THF (1.0 mL) was added. Tri-tert-butylphosphine (60 μί, 0.02 mmo with 10 wt% hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl) phenanthrene (6 mg, 5%) was prepared after purification. MS (ESI) m/z 5 315. HPLC purity at 210-370 nm 100.0%, 10.3 min.; Xterra® RP18 column, 3·5μ, 15〇χ 4.6 mm column, 1·2 mL/min., 85/15-5/95 (antic acid) Ammonium buffer pH = 3.5 / ACN + MeOH) was held for 4 minutes for 10 minutes. Example 18: Preparation of 1-methyl-5-[4-(1Η-pyrrol-1-ylsulfonyl)phenyl]-1H-10pyrrole-2-carbonitrile

Step 1: A slurry of sodium hydride (1·〇5 mL, 15.0 mmol) in dry THF (10 mL) was added at room temperature (0.71 g, 60% in mineral oil, 17.8 mmol )Inside. 4-Bromobenzenesulfonate (1.5 g, 6.0 mmol) dissolved in dry THF (5 mL) 15 was added dropwise. The reaction mixture was stirred overnight. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude material. The crude product was purified via an Isco chromatograph (RedisepTM column, dioxin 20, hexanes, EtOAc (EtOAc: EtOAc) -1H-pyrrole (0.27 g, 16%). MS (ESI) m/z 286. HPLC purity at 210-370 nm 100.0%, 9.9 min.; Xterra® RP18 column '3·5μ, 150 χ4·6 mm column, 1.2 mL/min., 85/15-5/95 47 200848019 (蠛The ammonium acid buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Step 2: According to the general procedure B, 1-[(4-bromophenyl)sulfonyl]-1H-pyrrole (250 mg, 0.87 mmol), 5-cyano-1-methyl-indole-ton-2 - boronic acid 5 (72 mg, 0.48 mmol), fluorinated clock (76 mg, 1.3 mmol), and ginseng (diphenylmethylene propyl I) di Ib (0) (10 mg, 0.01 mmol) Nitrogen was placed in an oven-dried flask and dry THF (1.0 mL) was added. Tri-tert-butylphosphine (60 μί, 0.02 mmo in hexane 1 〇 wt%) was added and the reaction was stirred for 16 hours. 1-Methyl-5-[4-(1Η-pyrrol-1-ylsulfonyl) 10 phenyl]-1H-pyrrole-2-carbonitrile (81 mg, 30%) was prepared after purification. MS (ESI) m/z 311. HPLC purity at 210-370 nm 100·0〇/〇, 11.6 min.; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1·2 mL/min., 85/15-5/ 95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 15 Example 19: Preparation of 4·(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethyl)benzenesulfonamide

Step 1: 4-Bromo-2-trifluoromethyl-benzenesulfonium (0.50 g, 1.54 mmol) and ammonia (10 mL, ca. 7 N in methanol) were stirred in a sealed tube for 20 hrs. hour. The reaction solution was vacuum concentrated on a Celite® reagent. The crude product was purified by Isco chromatography (RedisepTM column, sulphur dioxide, gradient of 5-50% ethyl acetate with hexane) to recover 4-bromo-2-(trifluoromethyl)benzene. Sulfonamide (0.46 g, 96%). MS (ESI) m/z 304. HPLC purity at 99 200848019 210-370 nm, 99.8%, 7.4 min·; Xterra8 RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) The agent pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Step 2 ·· According to the general procedure B, 4-bromo-2-(trifluoromethyl)benzenesulfonamide 5 (170 mg, 0.56 mmol), 5-cyano-1-methyl-1H-oral ratio - 2-Kispung acid (100 mg, 0.67 mmol), fluorinated clock (107 mg, 1.85 mmol), and ginseng (diphenylmethyleneacetone) dipalladium (0) (14 mg, 0.01 mmol) in nitrogen It was placed in an oven-dried flask and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (83 pL, 0.02 mmol and hexane 1 〇 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1·methyl-1H.pyrrol-2-yl)-2-(trifluoromethyl)benzenesulfonamide (34 mg, 18%) was prepared after purification. MS (ESI) m/z 329. HPLC purity at 210-370 nm, 98.6%, 9.1 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes and 15 minutes for 4 minutes. Example 20: Preparation of 4-(5-cyano-1-indenyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethyl)benzenesulfonamide

Step 1: 4-bromo-2-trifluoromethyl 20-phenylsulfonium chloride (0.50 g, 1.54 mmol) and dimethylamine (1 mL, 33% in ethanol) in a manner analogous to the general procedure A Stirring was carried out in a sealed tube for 16 hours. 4-Bromo-N,N-dimethyl-2-(trifluoromethyl)benzenesulfonamide (〇·41 g, 80%) was prepared after purification. MS (ESI) m/z 332. HPLC purity at 210-370 nm 1〇〇_〇%, 49 200848019 9.3 min. ; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/ 95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N,N-dimethyl-2-(trifluoromethyl-5-)benzenesulfonamide (186 mg, 0-56 mmol), 5-cyano-1-indenyl -1H-port ratio of each-2-pyrhenic acid (100 mg, 0.67 mmol), fluorinated clock (107 mg, 1.85 mmol), and ginseng (diphenylmethyleneacetone) di Ib (0) (14 Mg, 0.01 mmol) was placed in an oven-dried flask in nitrogen and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (83 pL, 0.02 mmol and 10 wt% of 10 hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethyl)benzenesulfonamide (115 mg, 58%) Prepared after purification. MS (ESI) m/z 357. HPLC purity at 210-370 nm 98.4%, 10.4 min.; Xterra® RP18 column, 3.5μ, 150 x 4·6 mm column, 1·2 mL/min·, 85/15-5/95 (antic acid) Money buffer 15 pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. Example 21: Preparation of 4_(5-cyano-1_methyl·1Η·pyrrol-2-yl)-N-methyl-2-(trifluorodecyl)phenylamine

Step 1: In a manner similar to the general procedure A, 4-bromo-2-trisylmethyl 20-phenylsulfonium chloride (0.50 g, 1.54 mmol) and decylamine (10 mL, 33% in ethanol) Stirring in a sealed tube lasted 16 hours. 4-Bromomethyl-2(trifluoromethyl)methanesulfonamide (0.44 g, 90%) was prepared after purification. MS (ESI) m/z 318. HPLC purity at 210-370 nm 1〇〇·〇〇/0,8.5 50 200848019 min· ; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1·2 mL/min·, 85/ 15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B,4·Bromo-N-methyl-2(trifluoromethyl)benzene 5 sulfonamide (178 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrole 2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (1〇7 mg, 1.85 mmol), and ginseng (diphenylmethyleneacetone) two (0) (14 mg, 0.01 mmol) Nitrogen was placed in an oven-dried flask and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (83 pL, 0.02 mmol, 10 10 wt% in hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethyl)benzenesulfonamide (90 mg, 47%) after purification Preparation. MS (ESI) m/z 343. HPLC purity at 210-370 nm 99.2%, 9.7 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) 15 pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 22: Preparation of 4-(5-cyano-1 -methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethyl)benzenesulfonamide

Step 1 ·According to the general procedure C ' 4-> odor-2-dimethyl--this stone page && gas 20 (0.50 g, 1.54 mmol) and diethylamine (0.40 mL, 3.85 mmol) The dry digas methane (2 mL) was stirred together for 16 hours. 4-Bromo-indole, hydrazine-diethyl-2(trifluoromethyl)benzenesulfonamide (0.46 g, 83%) was prepared after purification. MS (ESI) m/z 360. HPLC purity at 210-370 nm 100.0%, 1〇·1 51 200848019 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammonic acid ammonium buffer pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N,N-diethyl-2(trifluoromethyl-5-)benzenesulfonamide (201 mg, 0.56 mmol), 5·cyano-1-methyl- 1H-pyrrol-2-ylphosphonic acid (100 mg, 0.67 mmol), fluorinated clock (107 mg, 1.85 mmol), and ginseng (diphenylmethyleneacetone) di Ib (0) (14 mg, 0.01 mmol The flask was placed in an oven-dried flask and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (83 0·02 mmo b, 10 wt% of 10 hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethyl)benzenesulfonamide (100 mg, 46%) Prepared after purification. MS (ESI) m/z 385. HPLC purity at 210-370 nm 100.0%, 11.2 min.; Xterra® RP18 column, 3·5μ, 150 χ 4·6 mm column, 1·2 mL/min·, 85/15-5/95 ( Ammonic acid ammonium buffer 15 pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Example 23: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethyl)benzenesulfonamide

Step 1 ·· According to the general procedure C, 4-bromo-2-trifluoromethyl-benzenesulfonyl chloride 20 (〇·50 g, 1.54 mmol) and isopropylamine (0.35 mL, 3.85 mmol) in dry The gas methane (2 mL) was stirred together for 16 hours. 4-Bromo-N-isopropyl-2-(trifluoroindolyl)benzenesulfonamide (0.50 g, 95%) was prepared after purification. MS (ESI) m/z 346. HPLC purity at 210-370 nm 100.0%, 9.6 min.; 52 200848019

Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min_, 85/15_5/95 (ammonium formate buffer PH=3.5/ACN+MeOH) lasts 1 〇 minutes for 4 minutes. Step 2: According to the general procedure B' 4_-N-isopropyl-2-(trifluoromethyl) 5 benzenesulfonamide (193 mg, 〇·56 mmol), 5-cyano-1-methyl -1H-pyrrol-2-yl side acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and ginseng (diphenylmethyleneacetone) di Ib (0) (14 mg, 0 • 01 mmol) was placed in an oven-dried flask in nitrogen and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (83 pL, 0. 02 mmol, with 10 10 wt% of hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1_methyl-1H-pyrrole-2-yl)-N-isopropyl-2-(trifluoromethyl)benzenesulfonamide (91 mg, 44%) Then prepare. MS (ESI) m/z 371. HPLC purity at 210-370 nm 100.0%, 10.6 min·; Xterra® RP18 column, 3.5 μm, 150 χ 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate) Buffer 15 pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Example 24: Preparation of 4-(5-cyano-1-methyl·1Η·pyrrol-2-yl)-N-ethyl-2-(trifluoromethyl)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethyl-benzenesulfonate 20 (0.50 g, 1.54 mmol) and ethylamine (2.0 mL, 2.0 M in THF, 4.00 mmol) The mixture was stirred together in methyl chloride (2 mL) for 16 hours. 4-Bromo-N-ethyl-2-(trifluoromethyl)benzenesulfonamide (〇.5〇 g, 98%) was prepared after purification. MS (ESI) m/z 332. HPLC purity at 210-370 nm 53 200848019 100.0%, 9.1 min· ; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1·2 mL/min., 85/15-5/95 ( The ammonium acid buffer pH = 3.5 / ACN + MeOH was maintained for 10 minutes and held for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-ethyl-2-(trifluoromethyl)benzene 5-inosinamine (186 mg, 0.556 mmol), 5-cyano-1-methyl -1H·Phenol-2-yl side acid (100 mg, 0.67 mmol), fluorinated unloading (107 mg, 1.85 mmol), and ginseng (diphenylmethyleneacetone) dipalladium (0) (14 mg, 0.01 mmol) was placed in an oven-dried flask in nitrogen and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (83 μί, 0.02 mmol, hexane 10 10 Wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrole-2-yl)-N-ethyl-2-(trifluoromethyl)benzamine (90 mg, 45%) after purification Preparation. MS (ESI) m/z 357. HPLC purity at 210-370 nm 100.0%, 10.2 min.; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1·2 mL/min., 85/15-5/95 (ammonium formate) Buffer 15 pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Example 25: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethyl)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethyl-benzenesulfonium 20 (〇·50 g, 1.54 mmol) and propylamine (0.32 mL, 3.85 mmol) in dry dichloromethane (2 Stir together for 16 hours in mL). 4-Bromo-N-propyl-2-(trifluoromethyl)benzenesulfonamide (0·53 g, 100%) was prepared after purification. MS (ESI) m/z 346. HPLC purity at 210-370 nm 100.0%, 9.7 min.; 54 200848019

Xterra® RP18 column, 3.5μ, 150 x 4.6 mm column, ΐ·2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) lasts 10 minutes, keeps 4 minute. Step 2: According to the general procedure B, 4-bromopropyl 2 -(trifluoromethyl)benzene 5 sulfonamide (193 mg, 0.56 mmol), 5-cyano-1-methyl-1H-oral ratio - 2-Base boronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 185 mm 〇1), and ginseng (diphenylmethyleneacetone) dipalladium (〇) (14 mg, 〇〇1 mm〇1) It was placed in an oven-dried flask in nitrogen and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (83 g, 0.02 mmol, 1 Torr 10 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano- small methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethyl)benzenesulfonamide (68 mg, 33%) was prepared after purification . MS (ESI) m/z 371. HPLC purity at 210-370 nm 100.0%, 10.7 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium acid buffer) Agent 15 pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Example 26: Preparation of 1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethyl)phenylHH-pyrrole-2-carbonitrile

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethyl-benzenesulfonyl chloride 20 (0.50 g, 1.54 111111〇1) and oral piroxicam (0·32 mL, 3.85 mmol) were dried. The mixture was stirred for a period of 16 hours in dichloromethane (2 mL). 1-{[4·Bromo-2-(trifluoromethyl)phenyl]sulfonyl}pyrrolidine (〇·53 g, 96%) was prepared after purification. MS (ESI) m/z 358. HPLC purity at 210-370 nm 100.0%, 9.8 55 200848019 min· ' Xterra® RP18 tube; {: main, 3.5 μm, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammonic acid ammonium buffer pH = 3.5 / ACN + Me 〇 H) for 10 minutes, for 4 minutes. Step 2: In a manner similar to the general procedure b, i-{[4-bromo-2-(trifluoro-5methoxy)-based] sulphate is slightly determined (200 mg, 0.56 mmol), 5_ Cyano-1-methyl·1Η·pyrrol-2-ylboronic acid (1 ,, 0.67 mmol), fluorinated unloading (107 mg, 1.85 mmol), and ginseng (diphenylmethyleneacetone) Palladium (〇) (14 mg, 0.01 mmol) was placed in an oven dried flask and dried THF (1.4 mL). Tri-tert-butylphosphine (83 μί, 0.02 10 mmol) in hexane 1 〇 wt% was added and the reaction was stirred for 16 hours. Methyl-5-[4_(pyrrolidin-1_ylsulfonyl)>3_(trifluoromethyl)phenyl]-1Η-pyrrole_2_carbonitrile (117 mg, 54%) was prepared after purification. HRMS: Analytical estimate for C17H16F3N302S + H+, 384.09881; (ESI, [M+H]+) found value, 384.0991, HPLC purity at 210-370 nm 15 100.0%, 10.9 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 1 minute, held for 4 minutes. Example 27: Preparation of (5·cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethyl)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethyl-benzenesulfonate (〇.5〇g, 1.54 mmol) and cyclopropylamine (0.27 mL, 3.85 mmol) in dry di-methane ( Stir together for 2 hours in 2 mL). 4-Bromo-N-cyclopropyl-2-(tri 56 200848019 fluoromethyl)benzenesulfonamide (0.51 g, 96%) was prepared after purification. Ms (ESI) m/z 344. HPLC purity at 210-370 nm 100.0%, 9.3 min; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 12 mL/min., 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes and 5 minutes for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-cyclopropyl-2-(trifluoromethyl)benzene decylamine (193 mg, 0.56 mmol), 5-cyano-1-indenyl-1H- Oral pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and ginseng (diphenylmethylene propyl) bis I bar (0) (14 mg, 0.01 mmol ) was placed in an oven-dried flask in nitrogen 10 and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (83 pL, 0.02 mmol, 10% by weight of hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethyl)benzenesulfonamide (87 mg, 42%) Then prepare. MS (ESI) m/z 369. 15 HPLC purity at 99-370 nm, 99.6%, 10.3 min.; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1·2 mL/min·, 85/15_5/95 (ammonium formate buffer) The agent pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Example 28: Preparation of 4-(5-cyano-1-methyl-m-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromethyl)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and cyclopropylmethylamine (0 34 mL, 3·85 mm 〇l) The mixture was stirred together in dichloromethane (2 mL) for 16 hours. 4-Bromo-N-(cyclopropane 57 200848019 yl)-2-(trifluoromethyl)-benzenesulfonamide (0.50 g, 91%) was prepared after purification. MS (ESI) m/z 358. HPLC purity at 210-370 nm 100.0%, 9.8 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) 5 for 10 minutes, for 4 minutes. Step 2: 4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethyl)benzamine (200 mg, 0.56 mmol), 5-cyano in a similar manner to the procedure of procedure B -1-methyl-1H-portpirox-2-ylboronic acid (1〇〇mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and ginseng (diphenylmethyleneacetone) Palladium (〇) (14 mg, 10 〇·〇1 mmol) was placed in an oven-dried flask in nitrogen and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (83 μί, 0.02 mmol, hexane 1 〇 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrole(cyclopropylmethyl)-2-(trifluoromethyl)-benzenesulfonamide (106 mg, 53%) was prepared after purification. MS (ESI) m/z 15 383. HPLC purity: 200.0%, 10.8 min· at 210-370 nm; Xterra® RP18 column, 3_5μ, 150 χ 4.6 mm column, 1.2 mL/min., 85/15- 5/95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. Example 29: 4-(5-cyano small methyl-1H.pyrrol-2-yl)-N- Preparation of cyclobutyl 20 -2-(trifluoromethyl)benzophenone

Step 1: According to the general procedure C, 4_bromo-2-trifluoromethyl-benzenesulfonium chloride (0.50 g, 1.54 mmol) and cyclobutylamine (〇33 mL, 3.85 mmol) on dry 258 200848019 Dissipate within 6 minutes of burning (2 mL) for 16 hours. The 4-ring ring of DT-(difluoromethyl)sulfonamide (0-53 g, 96%) was prepared after purification. Ms (ESI) m/z 358. HPLC purity at 210-370 nm 1〇〇·〇〇/0,9 9 min; Xterm® RP18 column, 3·5μ, 150 x 4.6 mm column, L2 mL/min., 5 85/15-5 /95 (ammonium formate buffer pH=3.5/ACN+Me〇H) lasted 10 minutes for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-cyclobutyl 2 -(trifluoromethyl)benzenesulfonamide (200 mg, 0.56 mmol), 5-cyano-1-methyl-indole- πBilo 2_ boronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), 10 and ginseng (diphenylmethyleneacetone) dipalladium (0) (14 mg, 0·01 mmol ) was placed in an oven-dried flask in nitrogen and dried thf (1.4 mL) was added. Tri-tert-butylphosphine (83 μΐ^, 0·02 mmo was added to hexane 10 wt%) and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-σ ratio 11-2-yl)-N-cyclobutyl-2-(trifluoromethyl)benzoquintain (122 mg, 57% 15 series is prepared after purification. MS (ESI) m/z 383. HPLC purity at 210-370 nm 99.3%, 10.9 min.; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 30: Preparation of 4-(5-cyanophosphonyl-1H-pyrrol-2-yl)--3-fluorobenzenesulfonamide 20

Step 1: According to the general procedure A, 4-bromo-3-fluoro-benzenesulfonium chloride (0.40 g, 1.46 mmol) was stirred with ammonia (20 mL, ca. 7N in decyl alcohol) for 16 59 200848019 hours. 4-Bromo-3-fluorobenzenesulfonamide was prepared after purification (0.23 g, 61%). HRMS: Analytical estimate for C6H5BrFN02S, 252.920284; (EI, M+·) found, 252.9201. HPLC purity at 210-370 nm 100.0%, 7.5 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 5 mL/min·, 85/15-5/95 (ammonium formate buffer) Agent pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-3-fluorobenzenesulfonamide (150 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 Methyl), fluorinated clock (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) 10 dipalladium) (15 mg, 0.01 mmol) were placed in an oven-dried flask in nitrogen. Add dry THF (1.4 mL). Tri-tertiary butylphosphine (89 // L, 0.02 mmol) in hexane (1% wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1Η-σ-pyrrol-2-yl)-3-fluorophthalite yellow amine (29 mg, 18%) was prepared after purification. MS (ESI) 279. HPLC purity at 15 21〇-370 nm 100.0%, 8.6 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate) Buffer pH = 3.5 / ACN + MeOH) for 1 minute and held for 4 minutes. Example 31: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-methyl phenanthroline

Step 1: According to the general procedure A, 4-bromo-3-fluorobenzenesulfonium (0.40 g, 146 mmol) was stirred with methylamine (10 mL, 33% in ethanol) for 16 hours. 4-Bromo-3-fluoro-N-methylphenylamine (0.33 g, 85%) was prepared on a purified 60 200848019. HRMS: Analytical estimate for C7H7BrFN02S, 266.93649; (EI, M+.) found, 266.9376. HPLC purity at 210-370 nm 100.0 〇 / 〇, 8.7 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15_5/95 (ammonium formate buffer) 5 pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-3-fluoro-N-methylbenzenesulfonamide (158 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0-70 mmol), fluorinated clock (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) di Ib) (15 mg, 0. 01 mmol) were placed in nitrogen. 10 Dry the flask and add dry THF (1.4 mL). Tri-tert-butylphosphine (89 μί, 0.02 mmol, 10 wt% in hexane) was added and the reaction was allowed to proceed for 16 hours. 4_(5-Cyanocylinyl-1H.pyrrole-2yl)-3•fluoro-N-methylbenzenesulfonamide (53 mg, 31%) was prepared after purification. HRMS: Analytical estimate for C13H12FN302S, 293.046342; (EI, M+.) found, 15 293.0627. HPLC purity at 210-370 nm 99.5%, 8.2 min.; Xterra® RP18 column, 3·5μ, 150 X 4·6 mm column, 1·2 mL/min., 85/15-5/95 ( The ammonium formic acid buffer pH = 3.5 / ACN + MeOH) was maintained for 1 minute and held for 4 minutes. Example 32: Preparation of 4·(5-fluorenyl+methyl-;111_pyrrole_2-yl)_3_fluoroanthracene 2 Preparation of 20-methylbenzenesulfonamide

Step 1: According to the general procedure A, 4-bromo-3-fluoro-benzenesulfonium (0.40 g, 1.46 mmol) was stirred with monomethylamine (1 mL, 33% in ethanol) for a period of time. hour. 4-Bromo-3-fluorodimethylbenzenesulfonamide (0·36 g, 89%) was prepared after purification. HRMS: Analytical estimate for C8H9BrFN02S, 280.95214; (EI, M+.) found, 280.9516. HPLC purity at 210-370 nm 98.9%, 9.6 min.; Xterra® RP18 column, 3·5μ, 150 5 χ 4.6 mm column, 1.2 mL/min·, 85Π5-5/95 (antimonic acid buffer pH) =3.5/ACN+MeOH) lasted 10 minutes for 4 minutes. Step 2: According to the general procedure B, 4-bromo-3-fluoro_1^3_dimethylbenzenesulfonamide (166 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrole-2 - boronic acid (106 mg, 0.70 mmol), fluorination (113 mg, 1.95 mmol), and ginseng (di 10 benzylideneacetone) dipalladium) (15 mg, 0. 01 mmol) Nitrogen was placed in an oven-dried flask and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μί, 0.02 mmol, with 10 wt% of hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N,N-dimethylbenzenesulfonamide (51 mg, 28%) was purified on 15 system. HRMS: Analytical estimate for C14H14FN302S, 307.07907; (EI, M+.) found, 307.0786. HPLC purity at 210-370 nm 99.3%, 8.8 min.; Xterra® RP18 column, 3.5 μm, 150 X 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 20 Example 33: Preparation of 4-(5-methyl-1-methyl-1H-17-bis-2-yl)-N-ethyl-3-fluorobenzenesulfonamide

Step 1: Stir in accordance with the general procedure A, 4-bromo-3-fluoro-benzenesulfonate (〇.4〇g, 62 200848019 1.46 mmol) with ethylamine (5 mL, 10.0 mmol, 2.0 M in THF) It lasted for 16 hours. 4-Bromo-indoleethyl-3-fluorobenzenesulfonamide (0.38 g, 92%) was prepared after purification. HRMS: Analytical estimate for C8H9BrFN02S, 280.95214; (EI, M+·) found, 280.951. HPLC 5 purity at 210-370 nm 100.0%, 9.6 min_ ; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15_5/95 (ammonic acid buffer pH= 3.5/ACN + MeOH) lasted 10 minutes for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N_ethyl_3_fluorobenzenesulfonamide (166 mg, 0·59 111111〇1), 5-cyano-1-methyl-111-pyrrole- 2-Base boronic acid (106 10 mg, 0-70 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) dipalladium) (15 mg, 0.01 mmol) in nitrogen It was placed in an oven-dried flask and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μιη, 0.02 mmol, with 10 wt% of hexane) was added and the reaction was allowed to react for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-15-yl-3-fluorobenzenesulfonamide (44 mg, 24%) was prepared after purification. HRMS: Analytical estimate for C14H14FN302S, 307.07907; (EI, M+.) found, 307.0792. HPLC purity at 210-370 nm 99.5%, 8.7 min.; Xterra® RP18 column, 3.5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (antimonic acid buffer PH =3.5/ACN+MeOH) lasted 10 minutes and 20 minutes for 4 minutes. Example 34: Preparation of 4-(5·cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-3-fluorobenzenesulfonamide

63 200848019 Step 1: According to the general procedure C, 4-bromo-3-1-benzenesulfonium chloride (0.40 g, 1.46 mmol) and diethylamine (0.38 mL, 3.65 mmol) in dry dichlorocarbyl ( 5 mL) was stirred together for 16 hours. 4-Bromo-N,N-diethyl-3-fluorobenzenesulfonamide (0.41 g, 90%) was prepared after purification. HRMS: Analytical estimate of 5 QoHnBrFNOj, 308.98344; (EI, M+.) found value, 308.9822. HPLC purity at 210-370 nm 100.0%, 10.9 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium acid acrylate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 10 Step 2: According to the general procedure B, 4-bromo-N,N-diethyl-3-fluorobenzenesulfonamide (183 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrole- 2-Benzylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) (〇) (15 mg, 0_01 mmol) in nitrogen It was placed in an oven-dried flask and dried THF (1.415 mL) was added. Tri-tert-butylphosphine (89 pL, 0.02 mmol, 10% by weight of hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-3-fluorobenzenesulfonamide (46 mg, 23%) was prepared after purification . HRMS: Analytical value of C16H18FN302S + H+, 336.11765; (ESI, [M+H]+) found, 336.117. HPLC purity at 210-370 nm 20 99.7%, 9·7 min·; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammonic acid ammonium buffer pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. Example 35: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)_3_fluoro-N-isopropylbenzenesulfonamide 64 200848019

Step 1 ·According to the general procedure C, 4-Methyl-3-fluoro-benzene-purine (0.40 g, 1.46 mmol) and isopropylamine (〇·31 mL, 3.65 mmol) in dry dichloromethane (5 mL) ) Stir together for 16 hours. 4-Bromo-hydrofluoro-N-isopropylphthalide 5 decylamine (〇·4〇 g, 93%) was prepared after purification. HRMS: Analytical estimate of C9H"BrFN〇2S, 294.696779; (EI, M+.) found, 294.9665. HPLC purity at 210-370 nm 100.0%, 10.2 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium acid acrylate buffer) pH=3.5/ACN+MeOH) for 1 minute and 10 minutes for 4 minutes. Step 2 ·According to '^General procedure B' 4-> odor-3-gas-N-isopropylbenzene continual amine (174 mg, 0.59 111111〇1), 5-cyano-1-methyl-111 -pyrrole_2-ylboronic acid (1〇6 mg, 0.70 mmol), fluorinated clock (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) di Ib) (0) (15 mg, 0_01 Methyl) was placed in nitrogen in an oven-dried flask and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (89 g, 0.02 mmol, 10 wt% in hexane) was added and the reaction was allowed to proceed for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-isopropylbenzenesulfonamide (35 mg, 19%) was prepared after purification. HRMS: Analytical estimate for C15H16FN302S, 321.09472; (ΕΙ, Μ+·) found, 20 321.0948. HPLC purity at 210-370 nm 100.0%, 9.1 min.;

Xterra® RP18 column, 3.5μ, 150 X 4·6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) lasts 10 minutes, keeps 4 minute. 65 200848019 Example 36: Preparation of 4-(5-nitro-1-methyl-1H-ubi-2-yl)-3·gas-N-propyl benzenesulfonamide

Step 1: According to the general procedure C, 4-wet, -3-fluoro-benzene, xenon (0.40 g, 5 1.46 mmol) and propylamine (0·30 mL, 3.65 mmol) are dried with dichloromethane ( 5 mL) was put together for 16 hours. 4-Motro-3-fluoro-N-propyl benzene S-amine (0.39 g, 90%) was prepared after purification. HRMS: Analytical estimate, 294.667979; (EI, M+·) found, 294.9684. HPLC purity at 210-370 nm 100.0%, 10.3 min.; Xterra® RP18 10 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium acid buffer) The agent pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Step 2: According to the general procedure B, 4_bromo-3-fluoro-N-propyl benzenesulfonamide (174 mg, 0.59 mmol), 5-cyano-1-methyl·1Η-σpyrazole-2- Boronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylpyrano 15 methyl ketone) di Ib) (0) (15 mg, 0.01 mmol) in nitrogen It was placed in an oven-dried flask and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μί, 0.02 mmo in hexane 10 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1_methyl-111-pyrrole_2-yl)-3-fluoro-N-propylbenzenesulfonamide was prepared after purification. HRMS: Analytical estimate for C15H16FN302S 20, 321.09472; (El, M+.) found, 321.0947. HPLC purity at 210-370 nm, 99.7%, 9.3 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium acid ester buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. 66 200848019 Example 37: Preparation of 5-[2-fluoro-4-(pyrrolidin-1-ylsulfonyl)phenyl]-1-methyl-1Ήpyrrole-2-carbonitrile

Step 1 ·According to the "General procedure C' 4-> stinky-3-gas-benzene-like turtle gas (〇.4〇g 5 1·46 mmol) and oral pyridazine (0.30 mL, 3.65 mmol) to dry The methylene chloride (5 mL) was stirred together for 16 hours. 1-[(4-Bromo-3-fluorophenyl)-n-yl]pyrrolidine (0.43 g, 96%) was prepared after purification. HRMS: Analytical estimate of C10HuBrFNO2S, 306.967979; (EI, M+.) found, 306.968. HPLC purity at 210-370 nm 100.0%, 10.3 min.; 10 Xterra8 RP18 column, 3·5μ, 150 X 4·6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium acid buffer) The agent pH = 3.5 / ACN + MeOH) lasted 1 , minutes for 4 minutes. Step 2 · According to the general procedure Β ' 1-[(4-> odor-3-phenylphenyl) acid group] 17 piroxime (182 mg, 0.59 mmol), 5-cyano-1_methyl- lH-σ ratio succinyl 15 boric acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) (0) (15 mg, 0.01 mmol) It was placed in an oven-dried flask in nitrogen and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (89 pL, 0.02 mmol, 1% by weight of hexane) was added and the reaction was allowed to proceed for 16 hours. 5-[2_Fluoro-4-bbidol sigma small base yellow 20 fluorenyl)phenyl]-1-methyl-IH-u pyrrole-2-indene nitrile (61 mg, 31%) was purified Then prepare. HRMS: Analytical value of C16H16FN302S + H+, 334.10200; (ESI, [M+H]+) found value, 334.1035. HPLC purity at 210-370 nm 100.0%, 9.3 min·; Xterra® RP18 column, 3·5μ, 150 67 200848019 χ 4·6 mm column, 1·2 mL/min·, 85/15-5/ 95 (antimonate buffer pH = 3.5 / ACN + MeOH) was maintained for 10 minutes for 10 minutes. Example 38: Preparation of 4-(5-cyano-1-methyl-1H-pyrrole-2yl)cyclopropyl-3-fluorobenzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-3-fluoro-benzenesulfonium (0.40 g, 1.46 mmol) and cyclopropylamine (0.25 mL, 3.65 mmol) were combined with dry dichloromethane (5 mL) 16 hours of time to go. 4->Smell-N-cyclopropyl-3- gas phenoxide Yellow decylamine (0.37 g, 86%) was prepared after purification. HRMS: Analytical value of C9H9BrFN02S 10 - H+, 291.94486; (ESI, [M-Η]-) found, 291.9462. HPLC purity at 210-370 nm 100.0%, 9.8 min.; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium acid acrylate buffer) PH = 3.5 / ACN + MeOH) lasted 10 minutes for 4 minutes. 15 Step 2: According to the general procedure B, 4-bromo-N-cyclopropyl-3-fluorobenzenesulfonamide (175 mg, 0.59 mmol), 5-cyano-1-indenyl-1H-pyrrole-2- Boronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) di Ib) (0) (15 mg, 0.01 mmol) in nitrogen It was placed in an oven-dried flask and dried THF (1.4 mL) was added. 20 Tri-tert-butylphosphine (89 pL, 0.02 mmol, 1 〇 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-smallmethyl-1H-pyrrol-2-yl)cyclopropyl-3-fluorobenzamide (26 mg, 14%) was prepared after purification. MS (ESI) m/z 319. HPLC purity at 210-370 nm 100.0%, 8·9 68 200848019 min·; Xterra 8 RP18 column, 3·5μ, 15〇χ 4 6 tube column, i 2 mL/min·, 85/15-5 /95 (ammonium formate buffer pH = 3 5 / ACN + Me 〇 H) For 10 minutes, hold for 4 minutes. 5 Example 39: Preparation of cyano + methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide

Step 1 ·· According to the general procedure C, 4-bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclopropylmethylamine (〇·32眺, 3 65匪〇1) Chlorine 10 (5 mL) was scrambled together for 16 hours. 4-Bromo-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide (0.25 g, 55%) was prepared after purification. HRMS: Analytical estimate of CwHnBrFNC^S - H+, 3〇5 96〇51; (ESI, [M H]-) found value, 305.9603. HPLC purity at 210-370 nm 100.0%, 10.5 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 15 mL/min·, 85/15-5/95 (ammonium formate buffer) Agent pH = 3 5 / AcN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-(cyclopropylmethyl)_3_fluorobenzenesulfonamide (182 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrole-2 - boronic acid (106 mg, 0.70 mmol), fluorinated unloading (113 mg, 1.95 mmol), and ginseng 20 (diphenylpyridinium propyl I) di Ib) (0) (15 mg, 0.01 mmol) It was placed in an oven-dried flask in nitrogen and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μί, 0.02 mmol, with 10 wt% of hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrole 69 200848019 -2-yl)-N-(cyclopropenyl)·3-fluorophthalic acid amine (26 mg, 13°/〇) Prepared after purification. HRMS: Analytical value of C16H16FN302S + H+, 334.10200; (ESI, [M+H]+) found, 334.1024. 1^1^ purity at 210-370 nm 1〇〇.〇%, 9.4 11^11.;义【611^©1〇) 18 column, 3.50, 15〇5 X 4.6 mm column, 1.2 mL/ Min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) was maintained for 4 minutes for 10 minutes. Example 40: Preparation of 4-(5·cyanomethylmethyl-2-yl)-N-cyclobutyl-3-fluorobenzenesulfonamide

10 Step 1: According to the general procedure c, 4-bromo-3-fluoro-benzenesulfonium (0.40 g, 1.46 mmol) and cyclobutylamine (0.31 mL, 3.65 mmol) in dry dichloromethane (5 mL) ) Stir together for 16 hours. 4-Bromo-N-cyclobutyl-3_fluorobenzenesulfonamide (0.40 g, 89%) was prepared after purification. MS (ESI) m/z 308 HPLC HPLC purity at 210-370 nm 98.2%, 10.6 min.; Xterra8 RP18 15 column, 3·5μ, 150 x 4.6 mm column, 1·2 mL/min·, 85 /15-5/95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-cyclobutyl-3-fluorobenzenesulfonamide (182 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-yl Boric acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenyl 2 〇 methyl propyl ketone 0) (〇) (15 mg, 0·01 mmol) Nitrogen was placed in an oven-dried flask and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μί, 0.02 mmol, hexane 1 〇 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclo 70 200848019 Butyl-3-D-phenylamine (28 mg, 14%) was prepared after purification . HRMS: Analytical estimate for C16H16FN302S-H+, 332.07875; (ESI, [M-H]·) found value, 332.0867. HPLC purity at 210-370 nm 96.9%, 9.4 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1·2 5 mL/min., 85/15-5/95 (antic acid) Ammonium buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes over 10 minutes. Example 41: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-fluorobenzenesulfonamide

10 Step 1 ·According to the general procedure C, 4-wet-form-benzene-produced chlorine (〇.40 g, 1.46 mmol) and diethylamine (0.38 mL, 3.65 mmol) with dry dichloromethane (5 mL) was stirred together for 16 hours. 4-Bromo-N,N-diethyl-2-fluorobenzenesulfonamide (0.19 g, 43%) was prepared after purification. HRMS: Analytical value of C10H13BrFNO2S + H+, 309.99071; (ESI, 15 [M+H]+) found value, 309.9917. HPLC purity at 210-370 nm 100.0%, 9.6 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1·2 mL/min., 85/15-5/95 (ammonium formate) Buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2 · According to the general procedure B ' 4-> odor-N,N-diethyl-2- benzene, 20 amine (183 mg, 0.59 mmol), 5-cyano-1-methyl-1H- Oral ratio of each -2- quinic acid (106 mg, 0. 70 mmol), fluorinated clock (113 mg, 1.95 mmol), and ginseng (diphenylarbenium acetonide) (0) (15 mg , 0.01 mmol) was placed in nitrogen in 71 200848019 placed in an oven-dried flask and dried THF (1.4 mL) was added. Tri-tertiary butyl (89 pL, 0.02 mmol, 10% by weight of hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrole-2yl)-N,N-diethyl-2-indanbenzene (63 mg, 32%) was purified on 5 system. MS (ESI) m/z 335. HPLC purity at 210-370 nm 100.0%, 9.7 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 42: Preparation of 4-(5-cyano-1-methyl-1Η-σpyrrol-2-yl)-2-fluoro-N-isopropyl 10-phenylbenzamine

Step 1 ·According to the general procedure C ' 4 ·Bromo-2-fluoro-behenyl xanthine chloride (0.40 g, 1.46 mmol) and isopropylamine (0.31 mL, 3.65 mmol) in dry dichloromethane (5 mL) Stir together for 16 hours. 4-Bromo-2-fluoro-N-isopropylbenzenesulfonyl 15 decylamine (189 mg, 44%) was prepared after purification. MS (ESI) m/z 296. HPLC purity at 210-370 nm 100.0%, 10.6 min.; Xterra8 RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (antimonic acid buffer pH) =3.5/ACN+MeOH) lasted 1 minute and held for 4 minutes. Step 2: According to the general procedure B, 4-bromo-2-fluoro-N-isopropylbenzenesulfonamide 20 (177 mg, 0.59 mmol), 5-cyano-1_methyl-1H_pyrrole-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) dipalladium) (0) (15 mg, 0.01 mmol) were placed in nitrogen. Dry the flask in an oven and add dry THF (1.4 mL). Add 72 200848019 Tri-tert-butylphosphine (89 μ!^, 0.02 mmo) to hexane (1% by weight) and the reaction for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-2-fluoro-N-isopropylbenzenesulfonamide (24 mg, 13%) was prepared after purification. MS (ESI) m/z 321. HPLC purity at 210-370 nm 100.0%, 9.0 5 min· ; Xteira® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium acrylate buffer) Agent pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 43: Preparation of 4-(5·cyanocyanaminyl-iH-pyrrol-2-yl)-N-cyclopropyl-2_fluorobenzenesulfonamide

Step 1: According to the general procedure C, 4_bromo-2-fluoro-benzenesulfonate (〇.4〇g, 1.46 mmol) and cyclopropylamine (〇·25 mL, 3.65 mmol) with Capricorn Methane (5 mL) was stirred together for 16 hours. 4_Bromo-di-cyclopropyl-2-fluorobenzenesulfonamide (190 mg, 440/〇) was prepared after purification. Ms (ESI) m/z 294. 15 at 210·370 nn^ HPLC purity 98.6%, 1〇·2 min· ; Xterra® RP18 column '3·5μ, 150 χ 4.6 mm column, 1·2 mL/min·, 85/15-5/ 95 (antacid money buffer pH=3.5/ACN+MeOH) lasted 1 minute for 4 minutes. Step 2: According to the general procedure B, 4_bromoindole-cyclopropyl-2-fluorobenzamide (176 mg, 0.59 mmol), 5-cyano-1_indenyl]η" Boric acid (106 20 mg, 0.70 mmol), potassium fluoride (113 mg, 195 mm 〇1), and ginseng (diphenylmethyleneacetone) dipalladium) (〇) (15 mg, 0·01 mm〇1) Place in an oven-dried flask in nitrogen and add dry THF (1.4 mL). Add di-tert-butylphosphine (89 pL, 0.02 mmol, with hexane 1 〇 〇 /0) And stirring 73 200848019 The reaction was carried out for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)_N-cyclopropyl-2-fluorobenzenesulfonamide (45 mg, 24% Prepared after purification. MS (ESI) m/z 319. HPLC purity at 210-370 nm 100.0%, 8. 7 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column , 1.2 5 mL/min·, 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) lasted for 10 minutes for 4 minutes. Example 44 · 4-(5-gas-based-1 -Methyl-1H-11 ratio of benzyl-2-yl)-N-(cyclopropylmethyl)-2-fluorobenzamide

10 Step 1: According to the general procedure C, 4-bromo-2-fluoro-benzenesulfonate (0.40 g, 1.46 mmol) and cyclopropylmethylamine (0·31 mL, 3.65 mmol) as dry two gas Methane (5 mL) was stirred together for 16 hours. 4-Bromo-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide (0.18 g, 40%) was prepared after purification. MS (ESI) m/z 308. HPLC purity at 210-370 nm, 97.7%, 10·7 min.; 15 Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammonium Bicarb Buff. pH = 9.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide (181 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrole- 2-Based boron 20 acid (106 mg, 0.70 mmol), fluorinated clock (113 mg, 1.95 mmol), and ginseng (diphenylmethylene propyl hydrazine) di I bar) (0) (15 mg, 0.01 mmol) It was placed in an oven-dried flask in nitrogen and dried THF (1.4 mL) was added. Add tri-tert-butylphosphine (89 pL, 0.02 mmol, with hexane 10 74 200848019

Wt%) and the stirring reaction lasted for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide (20 mg, 10%) was prepared after purification system. MS (ESI) m/z 333. HPLC purity at 210-370 nm 100.0%, 11.4 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm 5 column, 1.2 mL/min., 85/15-5/95 (ammonium acid buffer) The agent pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Example 45: Preparation of 4-(5-methyl-1-methyl-1Η-σΐ;[:σ-2-yl)-N-cyclobutyl-2_fluorobenzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-fluoro-benzenesulfonium chloride (0.40 g, 1.46 mmol) and cyclobutylamine (0.31 mL, 3.65 mmol) in dry dichloromethane (5 mL) Stirring took 16 hours. 4-Bromo-N-cyclobutyl-2-fluorobenzenesulfonamide (192 mg, 43%) was prepared after purification. MS (ESI) m/z 308. 15 HPLC purity at 210-370 nm, 90.7%, 11.2 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium acid buffer) The agent pH = 3.5 / ACN + MeOH) was maintained for 1 minute and held for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-cyclobutyl-2-fluorobenzenesulfonamide (185 mg, 0.59 mmol), 5-cyano-1-methyl-hydrazine-oral ratio - 2-keshiponic acid (1〇6 20 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) dipalladium) (〇) (15 mg, 0·01 Methyl) was placed in an oven-dried flask in nitrogen and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μΐ^, 0.02 mmol, with hexane 1 〇 wt%) was added and stirred at 75 200848019 for 16 hours. 4-(5-Cyano-1-methyl-11^bi-2-yl)-N-% butyl-2-phenylbenzene hydrazide (25 mg, 13%) was prepared after purification. MS (ESI) m/z 333. HPLC purity at 210-370 nm 99.6%, 9.3 min·; Xterra® RP18 column, 3.5 μm, 150 X 4·6 mm column, 1.2 mL/min·, 5 85/15-5/95 (antic acid) Ammonium buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 46: Preparation of 4·(5-cyano-1·methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfonamide

Step 1: According to the general procedure A, 4-bromo-2-trifluoromethoxy-benzenesulfonium chloride (0.35 g, 1.03 mmol) was stirred with ammonia (10 mL, ca·7N in methanol): 16 hours. 4-Bromo-2-(trifluoromethoxy)benzenesulfonamide (0.33 g, 100%) was prepared after purification. MS (ESI) m/z 320. HPLC purity at 210-370 nm 100.0%, 8.0 min.; Xterra® RP18 column, 3·5μ, 150 15 χ 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium acid buffer) The agent pH = 3.5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. Step 2: According to the general procedure B, 4-bromo-2-(trifluoromethoxy)benzenesulfonamide (192 mg, 0.59 mmol), 5-cyano-1_methyl-1H-pyrrol-2-yl Boric acid (107 mg, 0.71 mmol), fluorination (113 mg, 1.95 mmol), and ginseng (di 20 benzylideneacetone) di Ib) (〇) (15 mg, 0.01 mmol) were applied in nitrogen Place in an oven-dried flask and add dry THF (1.4 mL). Tri-tert-butylphosphine (89 pL, 0.02 mmol, with hexane 1 〇 76 200848019 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-2-(triple methoxy)benzenesulfonamide (50 mg, 24%) was prepared after purification. MS (ESI) m/z 345. HPLC purity at 210-370 nm 100.0%, 8.4 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm 5 column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) The agent pH = 3.5 / ACN + MeOH) was maintained for 4 minutes. Example 47: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluorodecyloxy)benzenesulfonamide

10 Step 1: According to the general procedure A, 4-bromo-2-trifluoromethoxy-benzenesulfonium chloride (0.35 g5 1.03 mmol) and decylamine (1 mL, 33% in ethanol) in a sealed tube Stirring was carried out for 16 hours. 4-Bromo-N-methyl-2-(trifluoromethoxy)benzenesulfonamide (0.21 g, 61%) was prepared after purification. MS (ESI) m/z 334. HPLC purity at 210-370 nm 98.0%, 8.8 min_ ; Xterra® 15 RP18 column '3·5μ, 150 χ 4·6 mm column, 1·2 mL/min., 85/15-5/95 ( The ammonium formic acid buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes over 10 minutes. Step 2: According to the general procedure B, 4-bromo-N-methyl-2-(trifluoromethoxy)benzenesulfonamide (200 mg, 0.59 mmol), 5-cyano-1.methyl-1H- Bibi-2·20-based boric acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) II! Bar) (0) (15 mg, 0. 01 mmol) was placed in an oven dried flask and dried THF (1.4 mL). Tri-tert-butylphosphine (89 μί, 0.02 mmo in hexane 77 200848019 10 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-smallmethyl-1H-σpyrrol-2-yl)-N-indolyl-2-(trifluoromethoxy)benzamide (61 mg, 28%) Then prepare. MS (ESI) m/z 359. HPLC purity at 210-370 nm 99.6%, 9.0 min· ; Xterra8 RP18 column, 3·5μ, 150 X 5 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 48: Preparation of 4-(5-methyl-1-methyl)-N,N-dimethyl-2-(trifluoromethoxy)benzenesulfonamide

10 Step 1: According to the general procedure A, 4-bromo-2-trifluoromethoxy-benzenesulfonium (0.35 g, 1.03 mmol) and dimethylamine (10 mL, 33% in ethanol) in a sealed The tube was stirred for 16 hours. 4-Bromo-N,N-dimethyl-2-trifluoromethoxy-benzenesulfonamide (0.29 g, 81%) was prepared after purification. Μρ· 55-58 〇C. MS (ESI) m/z 348.14. 15 Step 2: According to the general procedure B, 4-bromo-N,N-dimethyl-2-trifluoromethoxy-benzophenone (209 mg, 0.59 mmol), 5-ranyl-1-la Base-1H-17 piroxa-2-ylphenolic acid (107 mg, 〇·71 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethylene acetonide) II bar) (15 mg, 0.01 mmol) was placed in an oven dried flask under nitrogen and dried 20 THF (1.4 mL). Tri-tert-butylphosphine (89 pL, 0.02 mmol and 10 wt% in hexane) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1·methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethoxy)benzenesulfonamide (73 mg, 32%) Prepared after purification. MS (ESI) m/z 373. HPLC purity at 1100% to 1978. 95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. Example 49: Preparation of 4-(5-cyano-1-methyl-1Η-ηylo-2-yl)-N-ethyl-2-(tris(5-fluoromethoxy)benzenesulfonamide

Step 1: According to the general procedure A, 4-bromo-2-trifluoromethoxy-benzenesulfonium chloride (0.35 g, 1.03 mmol) was stirred with ethylamine (5 mL, 10.0 mmol, 2.0 M in THF) over 16 hour. 4-Bromo-indole-ethyl-2-(trifluoromethoxy)benzenesulfonium 10 amine (0.23 g, 64%) was prepared after purification. MS (ESI) m/z 348. HPLC purity at 210-370 nm 100.0%, 9.3 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-ethyl-2(trifluoromethoxy) 15 phenylamine (208 mg, 0.59 mmol), 5-cyano-1-methyl-1H- Mouth ratio -2-

Boric acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) (0) (15 mg, 0.01 mmol) were placed in nitrogen Dry in an oven and add dry THF (1.4 mL). Tri-tert-butylphosphine (89 μg. 0.02 mmo in hexane 2 〇 1 〇 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-smallmethyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethoxy)benzenesulfonamide (40 mg, 18%) system. MS (ESI) m/z 373. HPLC purity at 210-370 nm 99.4%, 9.4 min·; Xterra® RP18 column, 3·5μ, 150 X 79 200848019 4.6 mm column, 1·2 mL/min·, 85/15-5/95 ( The ammonium formic acid buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes over 10 minutes. Example 50: Preparation of 4-(5-cyano-1 -methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(trifluoromethoxy)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethoxy-benzenesulfonium chloride (0.35 g, 1.03 mmol) and diethylamine (0.26 mL, 2.57 mmol) as dry di- methane (5 mL) was stirred together for 16 hours. 4-Bromo-N,N-diethyl-2-(trifluoromethoxy)benzenesulfonamide (0.38 g, 98%) was prepared after purification. MS (ESI) m/z 376. HPLC purity at 210-370 nm 100.0%, 10.4 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1·2 mL/min., 85/15-5/95 (ammonium formate) Buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N,N-diethyl-2-(trifluoromethyl15-oxy)benzenesulfonamide (225 mg, 0.59 mmol), 5-cyano-1- ·1Η_Pipyl-2-pyrhic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) (〇) mg, 0·01 mmol) was placed in an oven-dried flask in nitrogen and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μ [, 〇·〇 2 mmo b with 20 wt% 10 wt%) was added and the reaction was allowed to proceed for 16 hours. 4-(5-Cyano-1·methyl-1Η-^σ)-N,N-diethyl-2-(trifluoromethoxy)benzophenazine (98 mg, 42%) Prepared after purification. MS (ESI) m/z 401. In the 210_370 11111 book 1^purity 1〇〇.〇%,1〇.3111111.; along the catch_111>18 column, 3.50, 80 200848019 150 x 4.6 mm column, 1.2 mL/min·, 85/15 -5/95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 51: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropyl-2-(trifluoromethoxy)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethoxy-benzenesulfonium chloride (0.35 g, 1.03 mmol) and isopropylamine (0.21 mL, 2.57 mmol) as dry di-methane (5 mL) ) Stir together for 16 hours. 'Bromo-N-isopropyl-2-(trifluoromethoxy)benzenesulfonamide (0.29 g, 78%) was prepared after purification. MS (ESI) m/z 362. HPLC purity at 210-370 nm 100.0%, 9.8 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (antimonate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-isopropyl-2-(trifluoromethoxy-15-phenyl)sulfonamide (217 mg, 0.59 mmol), 5-cyano-1 decyl- ΙΗ-la-rol-2-ylboronic acid (107 mg, 0.71 mmol), fluorinated unloading (113 mg, 1.95 mmol), and ginseng (diphenylmethylene acetonide) que) (〇) (15 mg, 0.01 Methyl) was placed in an oven-dried flask in nitrogen and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μί, 0.02 mmol) in 20 hexanes (10 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-indenyl-lH-ubiha-2-yl)-N-isopropyl-2-(trifluoromethoxy)benzamine (79 mg, 35% ) Prepared after purification. MS (ESI) 387. HPLC purity at 210-370 nm 1 〇〇·〇°/〇, 9.8 min.; Xterra® RP18 column, 3·5!1, 150 81 200848019 X 4.6 mm column, 1.2 mL/min·, 85/ 15-5/95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 52: Preparation of 4-(5-cyano-1_methyl-1H-pyrrole-2yl)-indolyl-2-(trifluoromethoxy)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethoxy-benzenesulfonium chloride (〇·35 g, 1.03 mmol) and propylamine (0.21 mL, 2.57 mmol) as dry dichloromethane (5 mL) was stirred together for 16 hours. 4-Bromo-N-propyl-2-(trifluoromethoxy)benzamide (〇·37 g, 91%) was prepared after purification. MS 10 (ESI) m/z 362. HPLC purity at 210-370 nm 100.0%, 9.9 min·; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-propyl-2-(trifluoromethoxy) 15 benzenesulfonamide (217 mg, 0.59 mmol), 5-cyano-1-indenyl-1H -pyrrol-2-ylboronic acid (107 mg, 〇71 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) di I)) (0) (15 mg, 0.01 Methyl) was placed in an oven-dried flask in nitrogen and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μί, 0·02 mmol, hexane 20 10 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-Methyl-1Η·0-Bylo-2-yl)-1^-propyl-2-(tris-methoxy)benzamine (66 11^, 29%) Prepared after purification. MS (ESI) 387. HPLC purity at 210-370 nm 100.0%, 9·9 min·; Xterra® RP18 column, 3·5μ, 150 82 200848019 X 4_6 mm column, 1·2 mL/min., 85/15-5/ 95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. Example 53: Preparation of 1-mercapto-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluorophosphonio)phenyl]1Η-pyrrole-2-carbonitrile

Step 1 ·According to the general procedure C ' 4 - dimethyl-2-trifluoromethoxy-benzoic acid chloride (0.35 g, 1.03 mmol) and pyrrolidine (0.21 mL, 2.57 mmol) in dry dichloromethane (5 mL ) Stir together for 16 hours. 1_{[4_Bromo-2-(trifluoromethoxy)phenyl]-pyridyl}pyrrolidine (0.25 g, 65%) was prepared after purification. MS (ESI) m/z 374. HPLC purity at 210-370 nm 1〇〇_〇〇/0, 10.1 min· ; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1 2 mL/min·, 85/15-5 /95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-2-(trifluoromethoxy)phenyl]sulfonyl 15 yl}pyrrolidine (224 mg, 0.59 mmol), 5-cyano-1-methyl-1H- Pyrrole-2· quinic acid (107 mg, 0.71 mmol), fluorinated unloading (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) di Ib) (0) (15 mg, 0·01 Methyl) was placed in an oven-dried flask in nitrogen and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μΐ^, 0·02 mmol, with 20 10 wt% of hexane) was added and the reaction was stirred for 16 hours. 1-mercapto-5-[4-indolerolidin-1-ylsulfonyl)-3-(trifluoromethoxy)phenyl]-1H-pyrrole-2-carbonitrile (98 mg, 42%) Prepared after purification. MS (ESI) m/z 399. HPLC purity at 210-370 nm 100.0%, 1 〇·〇min.; Xterra® RP18 column, 3·5μ, 150 83 200848019 X 4.6 mm column, 1·2 mL/min·, 85/15-5 /95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 54: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethoxy-benzenesulfonium chloride (0.35 g, 1.03 mmol) and cyclopropylamine (0.17 mL, 2.57 mmol) were dried in dry air ( 5 mL) was given for 16 hours. 4-Moline-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide (0.25 g, 68%) was prepared after purification. MS (ESI) m/z 360. HPLC purity at 210-370 nm 100.0%, 9·5 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate) Buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-cyclopropyl-2-(trifluoromethoxy-15-phenyl)sulfonamide (216 mg, 0.59 mmol), 5-cyano-1-methyl- 1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) di Ib) (0) (15 mg, 〇· 〇ΐ mmol) was placed in an oven-dried flask in nitrogen and dry THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μί, 0.02 mmo in 2 〇 hexane 1 〇 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide (65 mg, 29%) Prepared after purification. MS (ESI) m/z 385. HPLC purity at 210-1370 nm 99.2%, 9·5 min·; Xterra® RP18 column, 3·5μ, 150 84 200848019 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 ( The ammonium formic acid buffer pH = 3_5 / ACN + MeOH) was maintained for 4 minutes. Example 55: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromethoxy)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethoxy-benzenesulfonium (0-35 g, 1.03 mmol) and cyclopropylmethylamine (0.21 mL, 2.57 mmol) as dry di-methane (5 mL) was disturbed together for 16 hours. 4-Bromo(cyclopropylmethyl)-2-(trifluoromethoxy)benzenesulfonamide (0.35 g, 91%) was prepared after purification. MS (ESI) m/z 374. HPLC purity at 210-370 nm 100.0%, 9.9 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Step 2: 4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethyl15-oxy)benzenesulfonamide (224 mg, 0.59 mmol), 5-cyano-1- Methyl-1H-pyridyl-2-pyrhic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and ginseng (diphenylmethylene propyl hydrazine) II Ib) 0) (15 mg, 0.01 mmol) was placed in an oven dried flask and dried THF (1.4 mL). Tri-tert-butylphosphine (89 μ, 0.02 mmo in 10 hexane 10 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-Methyl-1H-pyrrol-2-yl)-N-(cyclopropenyl)-2-(trifluoromethoxy)benzenesulfonamide (56 mg, 24%) Prepared after purification. MS (ESI) m/z 399. HPLC purity at 91-170 nm, 99.1%, 9.9 min·; Xterra® RP18 column, 3·5μ, 85 200848019 150 χ 4·6 mm column, 1.2 mL/min·, 85/15-5/95 ( The ammonium formic acid buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes over 10 minutes. Example 56: Preparation of (5-cyanocylinyl-1H-pyrrol-2-yl)-N-cyclobutyl-2(trifluoromethoxy)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethoxy-benzene is continuously brewed with chlorine (0.35 g, 1.03 mmol) and cyclobutylamine (〇·21 mL, 2.57 mmol) as dry di-methane (5 mL) was stirred together for 16 hours. 4-Bromo-N-cyclobutyl-2-(trifluoromethoxy)benzenesulfonamide (〇·23 g, 61%) was prepared after purification. MS (ESI) m/z 374. HPLC purity at 210-370 nm 10 〇.〇〇/. , 10.1 min· ; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, ι·2 mL/min_, 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) 10 minutes, keep for 4 minutes. Step 2: According to the general procedure B, 4-bromo-N-cyclobutyl-2-(trifluoropyridinyl15-yl)benzamine (224 mg, 0.59 mmol), 5-cyano-1-indenyl -lH-σ is slightly 2-pyrheptanoic acid (107 mg, 0.71 mmol), fluorinated clock (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) di-I) (〇) (15 Mg, 〇·〇ΐ mmol) was placed in an oven-dried flask in nitrogen and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (89 μί, 0.02 mmo in 10 hexane 10 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyloxa-2-yl)-N-cyclobutyl-2-(trifluoromethoxy)benzamide (56 mg, 24%) was prepared after purification . MS (ESI) m/z 399. HPLC purity at 210-370 nm 99. 4%, 1〇·〇min.; xterra8 RP18 column, 3·5μ, 150 86 200848019 χ 4.6 mm column, 1·2 mL/min_, 85/15-5 /95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. Example 57: Preparation of N-t-butyl butyl (5-cyano-1-methyl-1H-, pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2-trifluoromethoxy-benzene hydrazine chloride (0.35 g, 1.03 mmol) and tributylamine (〇·21 mL, 2.57 mmol) as dry dichloro Methane (5 mL) was stirred together for 16 hours. ‘N-T-butyl-2-(trifluoromethoxy)benzenesulfonamide (〇·33 g, 85%) was prepared after purification. MS (ESI) m/z 376. HPLC purity at 210-370 nm 100·0〇/〇, 10.2 min·; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1.2 mL/min·, 85/15-5/95 ( The ammonium formic acid buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes over 10 minutes. Step 2: According to the general procedure B, 4-bromo-N-tert-butyl-2-(trifluoromethyl15-oxy)phthalic acid amine (225 mg, 0.59 mmol), 5-cyano-1-methyl -1H-port ratio of each-2-yl side acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 111111〇1), and ginseng (diphenylmethylene propyl hydrazine) II | (〇) (1511^, 〇.〇1111111〇1) was placed in an oven-dried flask in nitrogen and dried THF (1.4 mL) was added. Tri-tert-butylphosphine (89 pL, 0.02 mmol and 10 wt% of 20 hexane) was added and the reaction was stirred for 16 hours. N-Tertibutyl-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfonamide (44 mg, 19%) Prepared after purification. MS (ESI) m/z 4 (H. HPLC purity: 99.0%, 10.1 min at 210-370 nm; Xterra8 RP18 column, 3 5μ, 87 200848019 150 x 4.6 mm column, 1.2 mL/min·, 85/15 -5/95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. Example 58: 4-(5-rangue-1 - methyl-1H-13 to 11 each -2 -yl)_2_(dimethylamine)-N,N-dimethylbenzenesulfonamide

Step 1: According to the general procedure A, 4-bromo-2-fluoro-benzenesulfonyl chloride (〇.4〇g, 1.46 mmol) and diamine (10 mL, 33% in ethanol) in a sealed tube Stirring took 16 hours. 4-Bromo-2-(dimethylamine)-N,N-dimethylbenzenesulfonamide (0.19 g, 42%) was prepared after purification. HRMS: 10 C10H15BrN2O2S + H+ analytical value, 307.01103; (ESI, [M+H]+) found, 307.012. HPLC purity at 210-370 nm 100.0%, 9.4 min.; Xterra8 RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (antimonic acid buffer pH) =3.5/ACN+MeOH) for 10 minutes, for 4 minutes 15 Step 2: According to the general procedure B, 4-bromo-2-(dimethylamine)-N,N-dimethyl stupin (180 mg , 0.59 mmol), 5 · cyano small methyl-1H-.倍略_2_ quinic acid (107 mg, 0.71 mmol), fluorinated (113 mg, 1.95 mmol), and ginseng (diphenylmethyleneacetone) dipalladium) (〇) (15 mg, 〇·〇ι Methyl) was placed in an oven-dried flask in nitrogen and dry THF 20 (Μ mL) was added. Tri-tert-butylphosphine (89 μί, 0.02 mmo in hexane 10 wt%) was added and the reaction was stirred for 16 hours. 4-(5-Cyano-1-methyl-1H-indole-2-yl)-2-(dimethylamine)-N,N-dimethylbenzenesulfonamide (28 mg, 14%) Prepared after purification. MS (ESI) m/z 332. 88 at 210-370 nm 200848019 HPLC purity 100.0%, 9.4 min.; Xterra® RP18 column, 3·5μ, 150 x 4.6 mm column, 1·2 mL/min·, 85/15-5/95 ( The ammonium formic acid buffer pH = 3.5 / ACN + MeOH) was maintained for 4 minutes over 10 minutes. Example 59: Preparation of 4-(5-cyano-1-methyl-1H-pyrrole-2yl)-2,5-difluoro-N-5-methylbenzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0·68 mmol) was stirred with methyleneamine in dichloromethane (1 mL) for 16 h. The reaction was followed by purification to provide 4-bromo-2,5-difluoro-N-methylbenzenesulfonium 10 amine (〇·17 g). HPLC purity at 210-370 nm 100.0%, 9.2 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium acid buffer) The agent PH = 3.5 / ACN + MeOH) lasted 10 minutes for 4 minutes. HRMS: Analytical estimate of C7H6Br*F2N02S - H+, 283.91979; 15 (ESI-FTMS, [M-Η]1·) found value, 283.92003. Step 2: According to the general procedure B, 4-bromo-2,5-difluoro-N-methylbenzenesulfonamide (143 mg, 0.5 mmol), 5-cyano-1-indenyl-1H-pyrrole-2 - boronic acid (90 mg, 0. 60 mmol), potassium fluoride (96 mg, 1.65 mmol), and ginseng (diphenylmethyleneacetone) dipalladium) (12 mg, 0.013 mmol) were placed in nitrogen Dry the flask in a 2-inch oven and add dry THF (1.3 mL). Tri-tert-butylphosphine (75 μί, 0.026 mmo in hexane 1 〇 wt%) was added and the reaction was stirred for 16 hours. Purification afforded 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)·2,5·difluoro-N-methylbenzenesulfonamide (24 mg). 89 at 210-370 nm 200848019 HPLC purity 87.6%, 8.4 min·; Xterra® RP18 column, 3·5μ, 150 x 4·6 mm column, 1.2 mL/min·, 85/15-5/ 95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) for 10 minutes, held for 4 minutes. HRMS: Analytical estimate of CuHnFsNsC^S _ H+, 310.04673; (ESI-FTMS, 5 [M-Η] 1-) found value, 310.04692. Example 60: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-isopropylbenzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2,5-difluorobenzenesulfonium chloride (0.20 10 g, 0.68 mmol) was stirred with isopropylamine in dichloromethane (1 mL) over 16 hr. The reaction was purified to afford 4-bromo-2,5-difluoro-N-isopropylbenzenesulfonamide (0.16 g). HPLC purity at 210-370 nm 96.6%, 10.7 min·; Xterra® RP18 column, 3.5 μm, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) 15 for 10 minutes, for 4 minutes. HRMS: Analytical estimate of C9H1()BrF2N02S - H+, 311.95109; (ESI-FTMS, [M-Η] 1-) found, 311.95114. Step 2: According to the general procedure B, 4-bromo-2,5-difluoro-N-isopropylbenzenesulfonamide (150 mg, 0.5 mmol), 5-cyano-1-methyl-1H. Bis-2-ylboronic acid 20 (90 mg, 0.60 mmol), potassium fluoride (96 mg, 1.65 mmol), and ginseng (diphenylarbenium acetonide) di Ib) (12 mg, 0.013 mmol) Nitrogen was placed in an oven-dried flask and dry THF (1.3 mL) was added. Tri-tert-butylphosphine (75 μί, 0.026 mmol, with 1 〇 wt%) and 90 200848019 were added to stir the reaction for 16 hours. Purification afforded 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-isopropylbenzenesulfonamide (24 mg). HPLC purity at 210-370 nm 97.2%, 9.3 min.; Xterra® RP18 column, 3·5μ, 150 χ 4·6 mm column, 1·2 mL/min., 85/15-5/95 ( The formic acid buffer pH 5 = 3.5 / ACN + MeOH) lasted 10 minutes for 4 minutes. HRMS: Analytical estimate for C15H15F2N302S - H+, 338.07803; (ESI-FTMS, [M-Η] 1-) found value, 338.07811. Example 61: Preparation of 4-(5-cyano-1-indenyl-1H-pyrrol-2-yl)cyclopropyl-2,5-difluorobenzenesulfonamide

Step 1: According to the general procedure C, 4-bromo-2,5-difluorobenzenesulfonium chloride (0.20 g, 0.68 mmol) was stirred with cyclopropylamine in di- methane (1 mL) for 16 hr. The reaction was purified to afford 4-bromo-N-cyclopropyl-2,5-difluorophthalein (0.17 g). HPLC purity at 210-370 nm 99.2%, 10.2 min.; 15 Xterra® RP18 column '3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium acid buffer) The reagent pH = 3.5 / ACN + MeOH) was maintained for 1 minute and held for 4 minutes. HRMS: Analytical estimate of C^HsBrF^C^S - H+, 301.993544; (ESI_FTMS, [M-H] 1-) found value, 309.994355. Step 2: According to the general procedure B, 4-bromo-N-cyclopropyl-2,5-difluorophthalein 20 decylamine (150 mg, 0.5 mmol), 5-cyano-1-methyl-1H- Pyrrol-2-ylboronic acid (90 mg, 0.60 mmol), potassium fluoride (96 mg, 1.65 mmol), and ginseng (diphenylmethaneacetone) (12 mg, 0.013 mmol) were applied in nitrogen. Place in an oven-dried flask and add dry THF (1.3 mL). 91 200848019 Tri-tert-butylphosphine (75 μί, 0.026 mmol, in hexane l〇 wt%) was added and the reaction was stirred for 16 hours. Purification afforded 4-(5-cyano-1-methylpyrrol-2-yl)-N-cyclopropyl-2,5-dioxabenzenesulfonamide (33 mg). HPLC purity at 210-370 nm 99.0%, 9·1 min· ; Xterra® RP18 column, 3·5μ, 150 5 x 4.6 mm column, 1·2 mL/min., 85Π5-5/95 (antic acid) The ammonium buffer pfj = 3_5 / ACN + MeOH) was maintained for 4 minutes for 10 minutes. HRMS: Analytical estimate of Ci5H13F2N3 〇2S _ H+, 336.02638; (ESI-FTMS, [Μ·Η] 1-) found value, 336.042247. Example 62: Preparation of 4-(5·cyano small methyl-1Η-pyrrol-2-yl)-indole-(cyclopropanemethyl)- 2,5-difluorobenzenesulfonamide (WYE-100761)

Step 1 ·According to the general procedure C ' 4-> odor-2,5-diqi benzene is indeed brewed with chlorine (〇.2〇g, 0.68 mmol) and cyclopropylmethylamine in dichloromethane (1 mL) Stir together for 16 hours. The reaction was purified to afford 4-bromo-N-(cyclopropylmethyl)-2,5-15 difluorobenzenesulfonamide (0.17 g). HPLC purity at 210-370 nm 95.0%, 9.3 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. HRMS: Analytical estimate of C1GH1()BrF2N02S - H+, 323.95109; (ESI-FTMS, [M-Η] 1-) found value, 20 323.95103. Step 2: According to the general procedure B, 4-bromo-N-(cyclopropylmethyl)-2,5-difluorophthalic acid amine (150 mg, 0.5 mmol), 5-cyano-1-methyl- 1H"bi-2-yl banolic acid (90 mg, 0.60 mmol), fluorinated clock (96 mg, 1.65 mmol), and ginseng 92 200848019 (diphenylmethyleneacetone) (12 mg, 0.013 mmol) It was placed in an oven-dried flask in nitrogen and dried THF (1.3 mL) was added. Tri-tert-butylphosphine (75 pL, 0.026 mmol, 10% by weight of hexane) was added and the reaction was stirred for 16 hours. Purification afforded 4-(5-cyano-1-indolyl 5 -1H-pyrrol-2-yl)·Ν-(cyclopropylmethyl)-2,5·difluorobenzenesulfonamide (47 mg). HPLC purity at 210-370 nm 98.2%, 9.5 min.; Xterra® RP18 column, 3·5μ, 150 X 4.6 mm column, 1.2 mL/min·, 85/15-5/95 (ammonium formate buffer) pH = 3.5 / ACN + MeOH) for 10 minutes, for 4 minutes. HRMS: Analytical estimate of C16H15F2N302S - H+, 350.07803; 10 (ESI-FTMS, [M-Η] 1-) found value, 350.07826. Example 63: Preparation of 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzene-sulfonamide

According to the general procedure B, 4-benzamine xanthine (472 mg, 2.0 mmol), 5-15 cyano-1-methyl·1 Η-^σ each-2-pyrine (360 mg, 2.4 mmol) , potassium fluoride (350 mg, 6.0 mmol), and ginseng (diphenylmethyleneacetone) two! Bar (48 mg, 0.05 mmol) was placed in an oven-dried flask in nitrogen and dry THF (5 mL) was added. Tri-tert-butylphosphine (0.30 mL, 0.1 mmo blended with 10 wt% of hexane) was added and the reaction was allowed to react for 16 hours. Purification afforded 4-(5-cyano-1-methyl-111-.pyr-2-yl)benzamine (190 mg). MS (ES) m/z 261.8; HPLC purity at 210-370 nm 99.6%, 7.1 min·; Xterra® RP18 column, 3·5μ, 150 χ 4.6 mm column, 1.2 mL/min·, 85 /15-5/95 (ammonium formate buffer pH = 3.5 / ACN + MeOH) 93 200848019 For 10 minutes, hold for 4 minutes. Example 64 - Effect of lutein and anti-lutein on alkaline phosphatase activity in T47D cells

5 This example was performed to identify lutein or anti-lutein by determining the effect of a compound on alkaline phosphatase activity in T47D cells. Materials and Methods: A·Reagents: 10 Medium: DMEM: F12 (1:1) (GIBCO, BRL), supplemented with 5% (v/v) activated carbon adsorption of fetal bovine serum (charcoal stripped fetal bovine serum) (non-thermal deactivated), 1 〇〇 U/mL penicillin, 100 pg/mL streptomycin, and 2 mM GlutaMaxTM reagent (GIBCO, BRL) 〇15 Alkaline phosphatase assay buffer: I. 0.1M Tris- HCl, pH 9.8, containing 0.2% Triton® X-1 oxime reagent II. II·〇·1Μ Tris-HCl, pH 9.8, containing 4 mM p-phenyl sulphate (Sigma). 20 B · Cell culture and treatment • The frozen T47D cell line was thawed in a 37 ° C water bath and diluted to 280,000 cells/mL in medium. 180 pL of the diluted cell suspension was added to each well of a 96-well plate (Falcon, Becton Dickinson Labware). Then add 2 〇μΙ of 94 200848019 diluted or diluted in the medium to reference or test compound 1 wells. #Testing for lutein antagonist activity, reference anti-lutein or test compound is added in the presence of 1 nM corpus luteum. The cell lines were incubated for 24 hours at 37. 0 in a 5% CO 2 /wet atmosphere. Note · For high throughput screening, a 5% concentration of each compound was tested at 〇·3 Kg/mLT. Based on the average molecular weight of 3 〇〇 g/mol of the compound in the library, the concentrate is approximately i μΜ. Next, the active compound was tested in a dose response assay to determine £(:5() and IC5〇. C. Qualitative luciferase assay: At the end of the treatment, the medium was removed from the pan. Add 5〇 (IL 10 assay buffer 1 to each well. Shake the plate in a titration plate shaker for 15 minutes. Add 15 分析 of analysis buffer η to each well. Optical density measurement is at 405 nM The test wavelength was measured at 5 minute intervals for 30 minutes. 15 Results Analysis - Analysis of Dose-Reaction Data About the reference and test compound, the rate (slope) of the dose (X-axis) relative to the enzyme reaction (Y-axis) One dose response curve. Use square root-transformed data for analysis of both agonist and antagonist patterns and nonlinear dose response curves. Use Huber weighting to drop 20 parts off the ontology (outlier) The role of the EC50 or ic50 value from the retransformation. One-way variation analysis and single-dose and dose-response studies using JMP software (SAS Institute, Ltd.) -4 Linear Dose Response Analysis. Reference Compound 95 200848019 Progesterone and trimegestone are reference lutein known in the art and typically exhibit about (U nM to about 2.0 nM EC5 (tRU486 is known in the art) A reference anti-lutein system and typically exhibits an IC50 of from about 0.1 nM to about 2.0 nM. EXAMPLES Active dose (nM) IC5〇(nM) 1 13.9 2 81.3 3 11.4 4 23.8 5 27.5 6 47.9 7 66.1 8 48.4 9 10000 10 146.5 11 132.2 12 189.1 13 13.9 14 6.6 15 58.9 16 40.8 17 27.6 18 48.1 19 35.8 20 81.9 21 22 80.4 23 77.1 24 45.8 25 17.3 26 115.1 27 38.2 28 34.9 29 17 30 91 31 8.5 96 200848019 32 127.8 33 13.1 34 65.6 35 26.8 36 26.5 37 150.7 38 9.7 39 40.4 40 18.1 41 62.2 42 48.1 43 30 44 45.6 45 99.4 46 75.8 47 48 62.7 49 121.5 50 101.1 51 32.5 52 8.4 53 22.7 54 71.7 55 12.3 56 30 57 30 58 25.9 59 36.1 60 49.3 61 30 62 163.8 63 99.5 All publications cited in the instructions are incorporated As a reference. Although the invention has been described with reference to the specific embodiments thereof, it is understood that modifications may be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the accompanying 5 patent application. 97 200848019 i: Simple description of the diagram 2 (none) [Description of main component symbols] (none) 98

Claims (1)

200848019 X. Patent application scope: h A compound with the following structure: Hv Η Wherein: R々R2 is selected from the following group: Η, CdC6 alkyl, substituted CiJX6 alkyl, cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, c3 to alkenyl, Q to C6 substituted alkenyl, ^ to decynyl, substituted 6 Cjc6 alkynyl '-(CHmXn)zCHpXq, 〇_CjC6 alkyl, 10 to C6 substituted alkyl, and 〇_(CHmXn)zCHpXq; or Ri and R2 may together form a ring of 4 to 8 ring atoms, It has a carbon atom and 1 to 4 N, Ο, S, or S02 in its main chain, and any C atom or N atom of the τ ring is selectively (^ to .alkyl, F, or CF3). Substituting; R3, R4, R5 and R6 are respectively selected from the group consisting of hydrazine, halogen, CN, <^ to (6 alkyl, substituted C^c6 alkyl, -( CHmXn)zCHpXq, (:3 to (:6 cycloalkyl, substituted C3 to C6 cycloalkyl, 〇-Ci to C6 alkyl, 〇_(^ to (:6 substituted alkyl, OH, NH2 , NH-(CHmXn)zCHpXq, CHCHmXJzCHpXq, N-{(CHmXn)zCHpXq}2' aryl, by Substituted aryl, heteroaryl, 99 20 200848019 10 2. 3. 15 4. 5. 6. 20 7. 8. Substituted heteroaryl, heterocyclic, and substituted heterocyclic; X-based halogen; m and η are 0 to 2, respectively, but conditionally m + η = 2; ρ and q are 〇 to 3, respectively, but conditionally ρ + q = 3; z is 0 to 10; R7 is selected from a group consisting of hydrazine, (^ to decyl, substituted (^ to decyl, C3 to C6 cycloalkyl, and substituted C3 to C6 cycloalkyl; or one of A pharmaceutically acceptable salt, tautomer, metabolite or prodrug. A compound according to claim 1 wherein R3, R4, 115 and 116 are oxime. A compound of claim 1 or 2 Wherein R4 or 115 is 11 or a halogen, for example, as in the compound of claim 1 or 2, wherein the compound is from the alkyl group to the alkyl group, for example, a methyl group, as in the first or second aspect of the patent application. a compound, wherein 1 is a group of 11 or (1 to C6 alkyl group. The compound of claim 1 or 2, wherein the group 112 is 11, (^ to C6 alkyl, substituted (^ to (: 6 alkyl) , C3 to C6 naphthenes A compound according to claim 1 or 2, wherein RHf, CH2-C3 to C8 cycloalkyl. As in the compound of claim 1 or 2, the center and 112 are combined 100 200848019 To form tetrahydropyrrole, pyrrolidine, piperidine, tetrahydropyran, morpholine, or π-pyrrol. 9. A compound of claim 1, wherein R34R6*h, ^' OCF3 'CF3, or N(CH3)2. 5 10. The compound of claim 1, wherein the heart is 11 or (^ to (6 alkyl; R2 is Η, (^ to (: 6 alkyl, substituted (^ to decane) a group, or a c3 to C6 cycloalkyl group; or a core and a ruler 2 are bonded with a N atom to form a tetrahydropyrrole, a σ bottom bite, a tetrahydro 0 ° base, a phenoline, or a π ratio; R3 and R6 Respectively hydrazine, halogen, CF3, hydrazine CF3, or n(CH3)2; or ^5yrm, R7 (^ to decyl. 15 20 u. The compound of claim i, which is selected from a group consisting of 4-(5-cyano small methyl oxo-2-yl) methyl ketofenamide; 4-(5-cyano-1-methyl-1H-pyrrole_2_ Base_ 4-(5-Akenyl minimethyl, qingyi-=amine 4 (5·cyano small methylpyramine^ meal 1 propyl benzoic acid; cyanocyano small methyl-2-yliso Propyl phenyl decylamine; 4-(5-cyano small methyl. (tetra) · 2 benzyl isobutyl amide; Wl_methyl-1 Η · (10) · 2 yl) · Ν • ethyl (1) Benzoic amine; 4 -(5-cyano small methyl-rn-翁_2_yl)_Ν,Ν_ decylamine; Ν-(t-butyl)-4-(5-cyano-1_甲美土尹, T丞_1心比咯_2_基)benzene 101 200848019 Sulfonamide; 1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile (l-methyl-5-[4-(pyrrolidin-) L-ylsulfonyl)phenyl]-lH-pyrr ole-2-carbonitrile) ; 1-methyl-5-[4-(Big 定-1-ylsulfonyl)benzene-5-yl]-1H-17 ratio - 2-methylcholine, 1-methyl-5-[4-(moffin-4-ylglycolyl)phenyl]-1H-pyrrole-2-carbonitrile; 4-(5-cyano-1) Mercapto-1H-pyrrol-2-yl)-N-cyclobutylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropylbenzene Sulfonamide; 4-(5-cyano-1-methyl-1H-pyrrole_2_yl)_N-deca-hexylbenzene, 4-(5-alkyl-1 _indolyl-1H-1: 7Bilo 10 base)-N-(2,2,2-trifluoroethyl)benzenesulfonamide; 4-(5-cyano-1-indenyl-1H- 17bi-2-yl)- N-(^-propylmethyl) phenanthrene, 1-methyl-5-[4-(1 Η-σpyr-1-ylsulfonyl)phenyl]-1Η-pyrrole_2_A Nitrile; 4-(5-cyano-1-methyl-lH-u-bi-2(yl)-2-(dimethyl)benzamine, 4-(5-carbyl-1- Methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethyl)benzenesulfonyl 15 amine; 4-(5-cyano-1-methyl-1H-pyrrole -2_yl)-N-methyl-2-(trifluoromethyl)benzenesulfonamide; 4-(5 -Cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-(disorganic methyl) phenanthrene, 4-(5-carbyl-1- Methyl-1Η-σ-pyrrol-2-yl)-indole_isopropyl-2-(dimethylmethyl) phenanthrene, 4-(5-hydroxy-1-methyl-1Η-pyrrole-2 -yl)-indole-ethyl-2-(trifluoromethyl)benzenesulfonamide; 20 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl- 2·(Trifluorodecyl) phenite yellow amine, 1-methyl-5-[4-(11 piroxicam-1 -based base)-3-(dihethane)phenyl] -1 Η·0 bilox-2-carbazide, 4-(5-alkyl-1 1-methyl _ 1 Η-. Bilo-2_yl)-oxime-cyclopropyl-2-(disorganic methyl) phenanthrene, 4-(5-methyl-1-methyl-1H-pyrrol-2-yl)-N -(cyclopropylmethyl)-2-(trifluoromethyl)benzenesulfonamide; 102 200848019 4-(5-methyl-1-methyl-1Η-indolyl-2-yl)-N-ring Butyl-2-(dimethylmethyl) benzenesulfonamide; 4-(5-cyano-1-indenyl-1H-pyrrol-2-yl)-3-fluorobenzenesulfonamide, 4-(5 _ gas-based 1-methyl-1 Η-σ-pyrrol-2-yl)-3- gas-N-methylphthalide xanthine; 4-(5-cyano-1-methyl-1H-pyrrole -2-yl)-3-fluoro-N,N-diin-5ylbenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl- 3-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-3_fluorobenzenesulfonamide; 4-(5 -cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-isopropylbenzenesulfonamide; 4-(5-cyano-1_methyl-111-pyrrole-2 -yl)-3- gas-N-propyl phenoxide yellow-brown amine, 5-[2-tranze-1-ylshielin 10 fluorenyl)phenyl]-1-methyl-1H-pyrrole-2-yl Nitrile; 4-(5·cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-3-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl -1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide; 4-(5-methyl-1-methyl-1Η- Bilo-2-yl)-Ν-ί 丁基 butyl-3- benzene benzoic acid amine, 4-(5-cyano-1-methyl-1 Η-pyrrol-2-yl)-Ν, Ν-二Ethyl-2-fluorobenzenesulfonyl-15 decylamine; 4-(5-cyano-1-methyl-1Η-pyrrol-2-yl)-2-fluoro-indole-isopropylbenzenesulfonamide; 4- (5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2-fluorobenzenesulfonamide; 4-(5-cyano-1-methyl-1H-pyrrole -2-yl)-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide; 4-(5-cyano-1.methyl-1H-pyrrol-2-yl)-indole- Base-2-gas benzene phthalamide, 4-(5-nitro-1-methyl-1 Η-σpyrrol 20 -2-yl)-2-(dimethoxymethoxy)benzenestone , 4-(5-methyl-1-methyl-1Η-pyrrol-2-yl)-indole-methyl-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1 -methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethoxy)benzenesulfonamide; 4-(5-cyano-1_methyl-1H- Pyrrol-2-yl)-N-ethyl-2-(tris-methoxy)benzamine, 4-(5-murine-1-methyl-1H-17 ratio _2_ 103 200848019 5 10 15 20 base) N,N-ethyl-2-(difluoromethoxy)benzene decylamine; 4-(5-aryl small methyl-1H-pyrrol-2-yl)_N_isopropyl Base_2_(trimethylmethoxy)benzenesulfonamide, 4-(5-cyano) -1-曱基_111_面_2_基)Good propyl-2<tris gas methoxy)phenylphosphonate π-methyl_5_[4 ten ratios „ _ _ _ _ _ _ _ _ Trifluoromethoxy)phenylHH-t each _2-carbonitrile; 4·(5·nitromethylmethylpyrrol-2-yl)-indole_cyclopropyl_2_(tri-"oxy) Phenylxanthine; noradyl heptamethyl-m-old-2-yl)_Ν.(cyclopropylmethyl) 2 (three gas a secret) stupid indoleamine; 4-(5·cyano MU ratio slightly -2- ketone·cyclobutyl-2-(trifluorodecyloxy)benzene decylamine; tert-butyl butyl-nitro-small sulphate 1H than s-l-yl)-2-(difluoromethoxy) Phenylxanthine; 4_(5-cyano^methyl-1H_old·2·yl)·2-methylamine)_N N-di-f-benzoic acid amine; 4-(5·cyano) 1·Methyl](tetra)fluorenyl-like difluoro-form methyl stupid amine 4 (5-cyano small methylanthene) _2_yl like two (four) t-propyl phenyl hydrazine; 4-(5_ Cyano + methyl. 2) propyl propyl-2,5-difluorobenzene hydrazine; 4_(5-cyano small methyl ΐΗ · each 'yl)-N_(cyclopropylmethyl · 2,5• difluorobenzamine; and one of the drugs, the acceptable salt, tautomer, metabolite or prodrug. The use of a compound of the above-mentioned item (1) is used for the manufacture of a drug for contraception, treatment or prevention of fibroids in a female in need thereof. Uterine fibroids (uterine lei〇my〇mata), endometrial tissue ectopic, dysfunctional hemorrhage, or polycystic "nose syndrome", providing hormone replacement therapy, or treatment cycle-related symptoms. The use of the scope of item 12, wherein the fibroids are uterus 104 200848019 fibroids. 14. The use of claim 12, wherein the symptoms associated with the cycle include psychological symptoms and physical symptoms. The use of the scope of claim 14 wherein the psychological symptoms include mood changes, irritability, anxiety, inattention, or loss of libido. 16. For the purposes of claim 14, wherein the body Symptoms include dysmenorrhea, breast tenderness, bloating, fatigue, or food cravings 〇10 17. A compound of any of claims 1 to 11 Use for the manufacture of a medicament for treating or preventing hormone-dependent cancer, stimulating food intake, or synchronizing estrus in a mammal in need thereof. Use, wherein the cancer is selected from the group consisting of endometrial cancer, breast cancer, uterine cancer, ovarian cancer, and prostate cancer. 19. A method for preparing a compound of formula I: Wherein: RjaR2 is separately selected from the group consisting of hydrazine, CiSQ alkyl, substituted C!SC6 alkyl, C3 to (:8 cycloalkyl, 105 20 200848019 substituted a to Q ring Alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, q to C6 alkenyl, C3 to c0 substituted alkenyl, fluorene to hydrazine Alkynyl, substituted (:3 to (:6 alkynyl, -(CHmXn)zCHpXq, 〇-CjC6 fluorenyl, 〇-c^c6 substituted alkyl, and 0-(CHmxn)zCHpXq; or Ri and R2 may together form a ring of 4 to 8 ring atoms having a carbon atom and 1 to 4 N, 〇, S, or S〇2 in its main chain, and any C atom or N atom system of the ring is selected. R3, R4, R5 and R6 are respectively selected from the group consisting of: Η 'self, CN, Cjc6 alkyl, substituted Alkyl ' _(CHmXn)zCHpXq 'C3 to C6 cycloalkyl, substituted A to c6 cycloalkyl, 〇_c^C6 alkyl, Q_Ci to Q substituted alkyl, OH, NH2, NH_(CHmXn )CH 〇-(CHmXn)zCHpXq,N_{(CHmXn)zCHpX Mountain, aryl, Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; X-based halogen; m and η are respectively 〇 to 2, with the proviso that m + n = 2 ; P and q are G to 3, respectively, but conditionally p + q = 3; z is 0 to 10; IM is selected from the group consisting of HAW alkyl, substituted base, found, and Substituted C3 to c6 cycloalkyl; 106 200848019 or one of pharmaceutically acceptable salts, tautomers, metabolites or prodrugs; the method comprises: (a) having HNRiR and the following structure A sulfonium 5-based reaction: Wherein: LG is a first leaving group; and D is a halogen or sulfonate; 10 (b) the product of step (a) is linked to a port comprising a second leaving group. Hehe. 20. The method of claim 19, wherein the first leaving group is Cl, Br, F, or the mouth of the mouth is 0. 21. The method of claim 19 or 20, wherein step (8) Further 15 contains a base. 22. The method of claim 21, wherein the base comprises sodium carbonate, potassium carbonate, cesium fluoride, potassium fluoride, or potassium phosphate. 23. The method of claim 19, wherein the arylsulfonyl group has the following structure: The method of claim 19 or 20, which comprises more than one equivalent of an amine. 25. The method of claim 19, wherein step (b) further comprises a catalyst. 5 26. The method of claim 25, wherein the palladium catalyst is tetrakis(triphenylphosphine) palladium (〇) or Ib benzylidene propyl g (palladium) Dibenzylidene acetone) in the presence of tributylphosphine. 27. The method of claim 19, wherein the pyrrole comprises a leaving group having the following structure: The method of claim 19 or 20, wherein the pyrrole comprises a leaving group derived from lithium diisopropylamide, a trialkyl borate, and a compound having the following structure: 29. The method of claim 28, wherein the trialkyl borate is trimethyl borate, triethyl borate, or triisopropyl borate. 108 200848019 VII. Designated representative map: (1) The representative representative of the case is: (). (None) (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 4